![VDAC1 function in cell death, with apoptosis inducers enhancing VDAC1 expression levels and oligomerization. A schematic representation of VDAC1 function in cell death-Different models for the release of apoptogenic proteins, such as Cyto c (purple) and AIF (yellow), are shown. (A) Proposed model suggesting that apoptotic stimuli or conditions cause enhanced VDAC1 expression via increases in [Ca 2+ ]i levels or transcription factors, leading to activation of the VDAC1 promoter. The increase in VDAC1 expression shifts the equilibrium towards the VDAC1 oligomeric state, forming a hydrophilic protein-conducting channel capable of mediating the release of apoptogenic proteins (e.g., Cyto c and AIF) from the mitochondrial IMS to the cytosol. (B) Mitochondrial Ca 2+ overload induces apoptosis. Ca 2+ transport across the OMM, as mediated by VDAC1, and then across the IMM, as mediated by the MCU, leads to Ca 2+ overload in the matrix. This, in turn, causes dissipation of the membrane potential, mitochondrial swelling, PTP opening, Cyto c/AIF release and the triggering of apoptotic cell death. (C) Bax/Bak oligomerization and activation, forming a route for Cyto c/AIF release. (D) Bax activation leads to its association with the OMM, followed by its oligomerization as a large oligomer/complex, forming a Cyto c/AIF-conducting channel. (E) The interaction of the pro-apoptotic protein Bax with VDAC1 forms hetro-oligomers that mediate Cyto c/AIF release. (F) Prolonged VDAC1 closure leads to mitochondrial matrix swelling and OMM rupture, resulting in the appearance of a non-specific release pathway for apoptogenic proteins.](https://www.researchgate.net/profile/Yakov-Krelin/publication/320259816/figure/fig5/AS:546914251018243@1507405926179/VDAC1-function-in-cell-death-with-apoptosis-inducers-enhancing-VDAC1-expression-levels_Q320.jpg)
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OPEN ACCESS | www.cell-stress.com 11 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
www.cell-stress.com
Review
ABSTRACT
This review presents current knowledge related to VDAC1 as a
multi-functional mitochondrial protein acting on both sides of the coin, regu-
lating cell life and death, and highlighting these functions in relation to dis-
ease. It is now recognized that VDAC1 plays a crucial role in regulating the
metabolic and energetic functions of mitochondria. The location of VDAC1 at
the outer mitochondrial membrane (OMM) allows the control of metabolic
cross-talk between mitochondria and the rest of the cell and also enables in-
teraction of VDAC1 with proteins involved in metabolic and survival path-
ways. Along with regulating cellular energy production and metabolism,
VDAC1 is also involved in the process of mitochondria-mediated apoptosis by
mediating the release of apoptotic proteins and interacting with anti-
apoptotic proteins. VDAC1 functions in the release of apoptotic proteins lo-
cated in the mitochondrial intermembrane space via oligomerization to form
a large channel that allows passage of cytochrome c and AIF and their release
to the cytosol, subsequently resulting in apoptotic cell death. VDAC1 also reg-
ulates apoptosis via interactions with apoptosis regulatory proteins, such as
hexokinase, Bcl2 and Bcl-xL, some of which are also highly expressed in many
cancers. This review also provides insight into VDAC1 function in Ca2+ homeo-
stasis, oxidative stress, and presents VDAC1 as a hub protein interacting with
over 100 proteins. Such interactions enable VDAC1 to mediate and regulate
the integration of mitochondrial functions with cellular activities. VDAC1 can
thus be considered as standing at the crossroads between mitochondrial me-
tabolite transport and apoptosis and hence represents an emerging cancer
drug target.
VDAC1 at the crossroads of cell metabolism, apoptosis
and cell stress
Varda Shoshan-Barmatz1,*, Eduardo N. Maldonado2 and Yakov Krelin1
1 Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-
Sheva, 84105, Israel.
2 Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA.
* Corresponding Author:
Prof. Varda Shoshan-Barmatz, Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel; Fax : 972-
8-647 2992; E-mail: vardasb@bgu.ac.il
VDAC ISOFORMS, STRUCTURE, AND CHANNEL ACTIVI-
TY
VDAC isoforms and cellular localization
Three different VDAC isoforms, VDAC1, VDAC2 and VDAC3,
sharing ~70% identity and structural and some functional
properties [1, 2], are expressed in mammalian mitochon-
dria, with VDAC1 being the major protein expressed. How-
ever, significantly differences in the functions of the three
isoforms were found [1, 3, 4], suggesting they assume dif-
ferent physiological roles [1, 5]. The three isoforms are
doi: 10.15698/cst2017.10.104
Received originally: 05.06.2017;
in revised form: 21.09.2017,
Accepted 22.09.2017,
Published 01.10.2017.
Keywords: apoptosis, cancer,
metabolism, mitochondria, VDAC1.
Abbreviations:
Aβ – Amyloid beta,
AD – Alzheimer’s disease,
ALS – amyotrophic lateral sclerosis,
AIF - apoptosis-inducing factor,
ANT - adenine nucleotide translocase,
Bcl-2 - B-cell lymphoma 2,
CSC – cancer stem cell,
CVD – cardiovascular disease,
Cyto c - cytochrome c,
DIDS - 4,4-diisothiocyanostilbene-2,2-
disulfonic acid,
HK – hexokinase,
IMM - inner mitochondrial membrane,
IMS – intermembrane space,
NSCLC - non-small cell lung cancer,
miRNA – micro RNA
OMM - outer mitochondrial
membrane,
OXPHOS – oxidative phosphorylation,
PTP - permeability transition pore,
RNAi - RNA interference,
ROS - reactive oxygen species,
TSPO - translocator protein,
T2D – type 2 diabetes,
VDAC - voltage-dependent anion
channel.
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 12 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
expressed in most tissue types, with VDAC1 expression
being higher than that of VDAC2 and VDAC3 in most but
not all tissues [1, 2].
Both VDAC1- and VDAC3-deficient mice are viable.
However, VDAC1−/− mice (inbred C57BL/6 background)
were born in less than expected numbers according to the
Mendelian ratio, suggesting partial embryonic lethality.
Studies using VDAC1−/− mice confirmed the importance of
this protein as a carrier of metabolites across the OMM [6].
In mice, deletion of VDAC1 and VDAC2 reduces respiratory
capacity [7], and the absence of VDAC3 causes male sterili-
ty, while a lack of both VDAC1 and VDAC3 causes growth
retardation [8] and is associated with deficits in learning
behavior and synaptic plasticity [9]. In this review, the fo-
cus will be on the VDAC1 isoform.
Using various approaches, VDAC was detected not only
in the mitochondria but also in other cell compartments [3],
such as the plasma membrane [3, 10], including the caveo-
lae and caveolae-like domains [11], the sarcoplasmic re-
ticulum (SR) of skeletal muscles [12], and the ER of rat cer-
ebellum [13, 14]. A possible mechanism for targeting VDAC
protein to the plasma membrane proposes that this ver-
sion of the protein contains an N-terminal signal peptide
responsible for targeting to the cell membrane [15, 16].
The exact function of extra-mitochondrial VDAC is un-
known, although several possible roles have been pro-
posed (reviewed in [17]).
VDAC1 structure, channel conductance, properties and
regulation
The three-dimensional structure of VDAC isoform 1 was
determined at atomic resolution, revealing that VDAC1 is
-strands connected by
-
being in parallel conformation along with a 25-residue-long
N-terminal region that lies inside the pore [18-20] (Fig.1A).
The N-terminal region is proposed to move in the open
space [21] and translocate from the internal pore to the
channel surface [22] (Fig.1B). This segment is ideally posi-
tioned to regulate the conductance of ions and metabolites
passing through the VDAC1 pore [20, 18].
The pore diameter of the channel has been estimated
to be between 3 and 3.8 nm [18], and is decreased to
about 1.5 nm when the N--helix is located within
the pore [18-20]. The stretch of multiple glycine residues
(21GlyTyrGlyPheGly25) [1, 5] connecting the N-terminal do-
-strand 1 of the barrel is thought to provide the
flexibility required for N-terminal region translocation out
of the internal pore of the channel [22]. The reported re-
sults suggest that the N-terminal region mobility is in-
volved in channel gating, interaction with anti-apoptotic
proteins, and VDAC1 dimer formation [22], as well as serv-
ing the interaction site of apoptosis-regulating proteins of
the Bcl-2 family (i.e., Bax, Bcl-2, and Bcl-xL) [22, 23-26] and
hexokinase (HK) [23, 27].
Purified and membrane-embedded VDAC1 is able to
assemble into dimers, trimers, tetramers, hexamers, and
higher-order moieties [1, 28-36]. The contact sites be-
tween VDAC1 molecules in dimers and higher oligomers
were identified [37]. Under physiological conditions,
VDAC1 is present as a monomer and dimer, with a contact
-strands 1, 2, and 19. However, upon apop-
tosis induction, VDAC1 dimers undergo conformational
changes to assemble into higher oligomeric states with
contact sites also -strands 8 and 16 [37]. VDAC1
oligomerization has been proposed to play important phys-
iological roles in the regulation of VDAC1 function, includ-
ing contributing to stabilizing the protein [38], serving as a
platform for other proteins that oligomerize, such as HK
[36] and creatine kinase [39], and finally, in mediating Cy-
tochrome c release and the binding of apoptosis-regulating
proteins [23, 28, 36] (see below).
FIGURE 1: Three-dimensional structure of VDAC1. VDAC1 mon-
omer and dimer structures. (A) Side-view of the crystal structure
of VDAC1 (PDB code: 3EMN). The -barrel is formed by 19
strands and the N-terminal domain (colored red) is folded into the
pore interior. (B) A proposed model for the conformation of
VDAC1 with its N-terminal on the outside of the VDAC1 pore. (C)
Top-view of VDAC1 dimer with the N-terminal helix nested inside
the VDAC1 pore in one monomer and outside of the pore in the
other. (D) Side-view of proposed dimer of VDAC1. Figures were
prepared using PyMOL software.
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 13 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
VDAC1 has been purified from mitochondria isolated
from liver, brain, and other tissues [40], and its channel
properties were characterized following reconstitution into
a planar lipid bilayer (PLB). Such bilayer-reconstituted
VDAC1 assumes a variety of voltage-dependent conducting
states, with different selectivities and permeabilities.
VDAC1 shows symmetrical bell-shaped voltage-dependent
conductance. At low voltages (-20 to +20 mV), VDAC1 ex-
ists in a high conductive state (~4 nS at 1 M KCl), and shows
a preference for transporting anions over cations, while at
high positive or negative potentials (> 40 mV), VDAC1
switches to lower conductance states permeable to small
ions [41, 42]. VDAC1 is permeable to small ions (e.g. Cl, K+,
Na+), and also to large anions, such as glutamate [41] and
ATP [43], and to large cations, such as acetylcholine and
dopamine [41].
The interactions of VDAC1 with Ca2+, ATP, glutamate,
NADH, and different proteins were suggested to modulate
its activity [44-47]. VDAC1 has been shown to be phos-
phorylated by protein kinase A (PKA) [48] and protein ki-
na ], and VDAC1 and VDAC2 were found to
be phosphorylated at a particular Tyr residue under hypox-
ic conditions [50].
VDAC1, A MULTI-FUNCTIONAL CHANNEL CONTROL-
LING CELL ENERGY AND METABOLISM
The OMM, the interface between the cytosol and a mito-
chondrion, is also a limiting boundary for modulating cell
bioenergetics, mediated via VDAC1. The metabolites and
ions that reach the matrix must first cross the OMM to
reach the mitochondrial intermembrane space (IMS), from
where they are then transported by about 53 secondary
transport proteins called mitochondrial carriers (MCs). The
mitochondrial carrier proteins of the family SLC25 (solute
carrier family 25, located in the inner mitochondrial mem-
brane (IMM)) are substrate-specific and mediate electro-
chemical, chemical and membrane potential gradient-
dependent transport. The SLC25 family includes carriers for
Pi (PiC), ADP/ATP (ANT) and aspartate/glutamate, pyruvate,
acyl carnitine, oxoglutarate, and citrate, among others [51].
On the other hand, VDAC1 is the sole channel mediating
the flux of ions, nucleotides and other metabolites up to
~5,000 Da (e.g. pyruvate, malate, succinate, NADH/NAD+)
across the OMM, as well as hemes and cholesterol [1, 52].
Thus, at the OMM, VDAC1 is perfectly positioned to func-
tion as gatekeeper for the entry and exit of substrates and
products into and out of the mitochondria, and to interact
with proteins that mediate and regulate the integration of
mitochondrial functions with other cellular activities [1, 29-
31, 42, 53, 54] (Fig. 2).
VDAC1 allows the shuttling of ATP/ADP and
NAD+/NADH, with mitochondria-generated ATP being
transported to the cytosol in exchange for ADP, which is
utilized in oxidative phosphorylation (OXPHOS) to generate
ATP. As such, VDAC1 controls the electron transport chain
[1] (Fig. 2), as well as the normal flow of metabolites [55].
The importance of VDAC1 in channeling ATP from the mi-
tochondria to kinases has been presented in several stud-
ies. These showed that VDAC1 interacts with HK and crea-
tine kinase (CrK) to convert newly generated ATP into high-
energy storage forms, like glucose-6-phosphate (G-6-P) and
creatine phosphate in brain and muscle, respectively. The
interaction of VDAC1 with HK mediates coupling between
OXPHOS and glycolysis, while at the contact sites between
the IMM and OMM, VDAC1 forms a complex with the ade-
nine nucleotide translocase (ANT), and CrK [56]. Dimeric
-tubulin was proposed as a regulator of VDAC1 permea-
bility to ATP, with -tubulin decreasing
the passage of ATP through the channel [57]. The im-
portance of VDAC1 in cell energy and metabolism homeo-
stasis is reflected in the findings that closure of VDAC [55]
or down-regulation of VDAC1 expression decreased me-
tabolite exchange between mitochondria and the cytosol
and inhibited cell growth [58, 59]. Moreover, VDAC1 is
overexpressed in many cancer cells [32], as discussed be-
low.
Cholesterol is another metabolite transported across
the OMM [60] (Fig. 2), with VDAC1 being considered as a
necessary component of a multi-protein complex, the
transduceosome, involved in the process. In addition to
VDAC1, the transduceosome also includes the OMM high-
affinity cholesterol-binding protein translocator protein
(TSPO) and the steroidogenic acute regulatory protein
(StAR) [61] (Fig. 2). Cholesterol synthesis is highly elevated
in various cancer cells, with hepatocellular carcinoma cells
containing 2-10-fold more mitochondrial cholesterol (main-
ly in the OMM) than found in liver mitochondria [62]. The
increased binding of HK to the mitochondria may increase
synthesis and uptake of cholesterol into the mitochondria
of cancer cells [63]. At high levels, cholesterol can reduce
the activity of membrane-associated proteins and thus
inhibit the metabolic functions of VDAC1 [64]. As such,
VDAC1 is involved in cholesterol synthesis and transport, as
well as being subject to cholesterol-mediated regulation.
Finally, it appears that VDAC1 is also part of a complex
mediating the transport of fatty acids through the OMM in
rat liver mitochondria [65]. In this case, it is hypothesized
that VDAC1 acts as an anchor, linking the long-chain acyl-
CoA synthetases (ACSLs) at the OMM to carnitine palmito-
yltransferase 1a (CPT1a), which faces the IMS. According to
the proposed model, upon activation by ACSL, VDAC1
transfers acyl-CoAs across the OMM to the IMS, where
they are converted into acylcarnitine by CPT1a. Moreover,
recently it was shown that fatty acid accumulation in
hepatocytes leads to a lack of phosphorylation by GSK-
indicating interplay between lipids and VDAC function [66].
Furthermore, it was recently proposed that VDAC behaves
as a lipid sensor [67].
CANCER, METABOLISM, MITOCHONDRIA, AND VDAC1
One of the main functions of the telomere is to prevent the
metabolic reprogramming in cancer cells that require plas-
ticity of the metabolic machinery, regardless of cellular or
tissue origin, a critical process that promotes cell prolifera-
tion with alterations seen in the metabolism of several
substrates, including glucose and glutamine [68, 69]. In the
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 14 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
FIGURE 2: VDAC1 as a multi-functional channel involved in metabolite, cholesterol and Ca2+ transport, energy production and in ER-mitochondria struc-
tural and functional association. The functions of VDAC1 in cell life include control of the metabolic cross-talk between the mitochondria and the rest of the
cell energy production, regulation of glycolysis via binding of HK, Ca2+ signaling and cholesterol transport. The various functions of VDAC1 in the cell and
mitochondria functions are presented. These include: 1. Control of the metabolic cross-talk between mitochondria and the rest of the cell; 2. Transport of
Ca2+ to and from the IMS and acting in Ca2+ signaling; 3. Lipid metabolism; 4. Transport of ions, such as Mg2+, Zn+, Na+ and K+; 5. Mediating cellular energy
production by transporting ATP/ADP and NAD+/NADH and acyl-CoA (FA-CoA) from the cytosol to and from the IMS, and regulating glycolysis via association
with HK; 6. Structurally and functionally contributing to ER-mitochondria contacts, mediating Ca2+ transport from the ER to mitochondria. Ca2+ influx and
efflux systems in the IMM are shown. The mitochondrial Ca2
+ uniporter (MCU), in association with a calcium-sensing accessory subunit (MCU1), mediates
Ca2+ transport from the IMS into the matrix. The ryanodine receptor (RyR) in the IMM mediates Ca2+ influx. NCLX, a Na+/Ca2+ exchanger, mediates Ca2+ efflux
from the matrix to the IMS. High levels of matrix Ca2
+ trigger the opening of the PTP, a fast Ca2+ release channel. Molecular fluxes are indicated by arrows.
The function of Ca2+ in regulating energy production is mediated via activation of the TCA cycle enzymes pyruvate dehydrogenase (PDH), isocitrate dehydro-
genase (ICDH) and -ketoglutarate dehydrogenase (-KGDH), leading to enhanced activity of the TCA cycle. The electron transport chain (ETC) and the ATP
synthase (FoF1) are also presented. VDAC1 mediates the transfer of acyl-CoAs across the OMM to the IMS, where they are converted into acylcarnitine by
-oxidation. VDAC1 is involved in cholesterol transport by being a constituent of a multi-protein complex, the transduceo-
some, containing StAR/TSPO/VDAC1.The ER-mitochondria association is presented with key proteins indicated. These include the inositol 3 phosphate recep-
tor type 3 (IP3R3), the sigma 1 receptor (Sig1R) (a reticular chaperone), binding immunoglobulin protein (BiP), the ER HSP70 chaperone, and glucose-
regulated protein 75 (GRP75). IP3 activates IP3R in the ER to release Ca2+ that is directly transferred to the mitochondria via VDAC1.
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 15 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
, Otto Warburg demonstrated increased lactic acid
production resulting from high glycolysis in tumors, as
compared to non-proliferating cells. The Warburg effect
described a metabolic phenotype characterized by en-
hanced glycolysis and suppression of mitochondrial me-
tabolism at any level of oxygen. However, although en-
hanced glycolysis is a prominent feature of most tumor
cells, the mitochondria of cancer cells maintain a mem-
brane potential, oxidize respiratory substrates, and gener-
ate NADH and ATP, among other functional parameters
[70-73]. The view of cancer as a metabolic disease that
originated with the experiments of Otto Warburg was
gradually displaced by the concept of cancer as a genetic
disease. Recently, evidence supporting a general hypothe-
sis that genomic instability and essentially all hallmarks of
cancer, including aerobic glycolysis, can be linked to im-
paired mitochondrial function and energy metabolism, has
been reviewed [74, 75]. Interestingly, no specific gene mu-
tations or chromosomal abnormalities are common to all
cancers [76], while nearly all cancers display aerobic gly-
colysis, regardless of their tissue or cellular origin. The view
of cancer as primarily being a metabolic disease will impact
approaches to cancer management and prevention.
Malignant cancer cells typically display high rates of
glycolysis, even when fully oxygenated (aerobic glycolysis),
and an altered redox balance [77-79]. To increase glycolysis,
cancer cells up-regulate the transcription of genes involved
in the glycolytic pathway (i.e., glucose transporters, glyco-
lytic enzymes, etc.). Cancer cells in fact use both glycolysis
and OXPHOS, with the ratio depending on the prevalent
normoxic or hypoxic environmental conditions and their
capacity to express adequate levels of oncogenes and tu-
mor suppressor gene products for cell growth [80]. By reg-
ulating the metabolic and energetic functions of mitochon-
dria, VDAC1 can, therefore, control the fate of cancer cells.
Mitochondrial-bound HK, considered the rate-limiting en-
zyme of glycolysis, is over-expressed in cancer [1, 81, 82].
The association of HK with VDAC1 offers several ad-
vantages to cancer cells [1, 32], such as direct access to
mitochondrial sources of ATP, assumption of the role of an
anti-apoptotic protein, reducing intracellular levels of reac-
tive oxygen species (ROS) and increasing synthesis and
uptake of cholesterol. The HK-VDAC1 complex formation is
regulated by Akt [83] and glycogen synthase kinase 3 beta
-VDAC complex is disrupted by VDAC
phosphorylation [84].
In recent years, cumulative evidence indicates that free
tubulin in cancers cells interacts with VDAC [70, 85]. Dimer-
-tubulin decreases the conductance of bilayer-
reconstituted VDAC1 and VDAC2 and also decreases respi-
ration in cardiac myocytes and isolated brain mitochondria
[86, 87]. In cancer cells, microtubule destabilization in-
duced by colchicine or microtubule stabilization by
paclitaxel increased and decreased free tubulin, leading to
decreased and ]. The dy-
ee tubulin appears to occur
only in cancer cells. It has been proposed that the dynamic
-tubulin heterodimers modulating
VDAC conductance (Fig. 3) [70].
VDAC1 and VDAC2 isolated after VDAC2/3 or VDAC1/3
double knockdown in cancer cells were shown to be sensi-
tive to tubulin inhibition. Even more, VDAC1 knockdown in
i-
cal for the n-
dogenous free tubulin [85]. Inhibition of VDAC1 conduct-
ance by free tubulin is a main contributor to the suppres-
sion of mitochondrial metabolism in the Warburg pheno-
type. Recently, the VDAC-tubulin interaction was proposed
to serve as a metabolic switch to increase or decrease mi-
tochondrial metabolism, ATP generation and cytosolic
ATP/ADP ratios [88]. High and low cytosolic ATP/ADP ratios
inhibit or favor aerobic glycolysis, respectively. Thus,
blockage of the inhibitory effect of tubulin on VDAC by
VDAC-tubulin antagonists promotes mitochondrial me-
tabolism and reverses the Warburg phenotype (Fig. 3). The
VDAC-tubulin interaction represents a new pharmacologi-
cal target for the development of novel anti-cancer agents
[88].
Silencing VDAC1 expression reduces cell energy homeo-
stasis, inhibiting cells and tumor growth
As cellular metabolic and energy reprogramming are can-
cer hallmarks essential for tumor progression, and VDAC1
is a key regulator of these processes [1, 30, 32, 47, 52, 89],
down-regulation of VDAC1 expression is expected to im-
pact cancer cell growth. VDAC1 down-regulation results in
reduced metabolite exchange between the mitochondria
and the cytosol, leading to inhibited cell growth. Indeed,
silencing VDAC1 expression reduced cellular ATP levels and
cell growth, with tight correlation between cell growth and
cellular ATP levels being seen [58]. shRNA directed against
hVDAC1 inhibited the development of a HeLa cervical tu-
mor [90]. Nano-molar concentrations of a single siRNA
specific to human VDAC1 silenced VDAC1 expression and
inhibited the growth of various cancer cell types. In fact,
such treatment inhibited solid tumor development and
growth in lung cancers (over 90%) both in vitro and in vivo
[59].
Recently, a global change in tumor hallmarks upon si-
lencing VDAC1 expression was demonstrated in glioblas-
toma multiform (GBM) [91]. Using a sub-cutaneous or an
intracranial-orthotopic GBM model, we demonstrated that
si-VDAC1 inhibited tumor growth, with the residual tumor
showing reversed oncogenic properties, such as repro-
gramed metabolism, angiogenesis, epithelial-mesenchymal
transition (EMT), invasiveness and stemness, leading to
differentiation into neuron- and astrocyte-like cells [91]
(Fig. 4). These VDAC1 depletion-mediated effects involved
alterations in transcription factors (TFs) that regulate sig-
naling pathways associated with cancer hallmarks, allowing
for attacks on the interplay between metabolism and on-
cogenic signaling networks (to be explored here), leading
to cancer stem cell (CSC) differentiation into neuronal-like
cells [91].
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 16 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
microRNA-mediated regulation of VDAC1
A number of microRNAs (miRNAs) targeting VDAC1 were
reported and found to be modified under pathological
conditions. miR-29a [92] and miR-320a [93] have been
shown to reduce VDAC1 expression levels. Another miRNA
species, miR-7, was shown to inhibit VDAC1 expression,
proliferation and metastasis in hepatocellular carcinoma
[94], possibly by affecting the permeability transition pore
(PTP) [95]. Recently, lncRNA-H19/miR-675 was reported to
regulate high glucose-induced apoptosis by targeting
VDAC1, and thus provides a novel therapeutic strategy for
the treatment of diabetic cardiomyopathy [96].
The therapeutic potential of a number of miRNAs able
to regulate VDAC1 expression levels is clear in view of the
observation that VDAC1 over-expression is associated with
a variety of pathological conditions, including Alzheimer's
disease (AD) [97-99], and cardiovascular diseases (CVDs)
[100]. In addition, hyperglycemia has been shown to in-
crease -cells [101] and in the kidney
[102].
FIGURE 3: VDAC1-tubulin interaction: a metabolic switch to modulate mitochondrial metabolism in cancer cells. In cancer cells, high levels of
free tubulin close VDAC1, decreasing the flux of metabolites, ATP and ADP through the OMM. VDAC1 closing leads to low generation of mito-
chondrial ATP and subsequently, to a low cytosolic ATP/ADP ratio that favors glycolysis in the Warburg phenotype. Erastin, a VDAC-tubulin
antagonist, opens VDAC1 by blocking the inhibitory effect of free tubulin. VDAC1 opening leads to increased mitochondrial metabolism and to a
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 17 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
FIGURE 4: VDAC1-depletion and metabolic reprogramming leading to alterations in key transcription factor levels and biological process-
es: a reversal of oncogenic properties and cell differentiation. (A) A schematic presentation of mitochondria in a cancer cell before treat-
ment with hVDAC1 siRNA. Here, cancer cells maintain homeostatic energy and metabolic states, with HK bound to VDAC1 accelerating gl y-
colysis and mitochondrial function to allow sufficient ATP and metabolite precursor levels to support cell growth and survival. (B) VDAC1
depletion leads to dramatic decreases in energy and metabolite generation. This leads to changes in master metabolism regulator (p53,
HIF1- c-Myc and NF-kb, P65) expression levels, which alters the expression of transcription factors associated with stemness, EMT, cell
proliferation, invasion, TAMs and angiogenesis, while leading to differentiation into astrocyte- or neuron-like cells.
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 18 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
VDAC1 AS A PLAYER IN MITOCHONDRIA-MEDIATED
APOPTOSIS
Programmed cell death, or apoptosis, is the biological pro-
cess by which a cell rapidly proceeds towards death upon
receiving specific stimuli. The apoptotic machinery in hu-
mans consists of a molecular network comprising a large
number of proteins that regulate a cascade of events lead-
ing to apoptosis through multiple parallel pathways. It is
well accepted that mitochondria serve as integrators and
amplifiers of apoptosis by mediating and regulating the
release of pro-apoptotic proteins and/or disrupting cellular
energy metabolism [103]. Upon transfer of an apoptotic
signal into the cell, mitochondrial membrane permeability
changes so as to facilitate the release of apoptogenic pro-
teins, such as cytochrome c (Cyto c), apoptosis-inducing
factor (AIF), and SMAC/Diablo, from the IMS into the cyto-
sol [54, 103]. These proteins participate in complex pro-
cesses, resulting in the activation of proteases and nucle-
ases, leading to protein and DNA degradation and cell
death. However, it remains unclear how these apoptotic
initiators cross the OMM and are thus released into the
cytosol. Several hypotheses regarding the mechanism of
mitochondria-mediated apoptosis have been proposed (Fig.
5) (for reviews, see [1, 30, 104]). The major models include
OMM rupture and non-specific release of IMS proteins into
the cytosol [55, 105, 106], opening of the PTP in response
to over-production of ROS or Ca2+ overload [107], a large
channel formed by Bax and/or Bak oligomers [108, 109], a
channel formed by hetero-oligomers of VDAC1 and Bax
[110, 111] or VDAC1 oligomers (Fig. 5) [23, 28-31, 36, 104,
112, 113].
All of the apoptotic proteins known to translocate to
the cytoplasm following an apoptotic stimulus reside in
IMS. Thus, only the permeability of the OMM needs to be
modified for their release [114-117]. Hence, VDAC1, as an
OMM channel, could mediate Cyto c release. Indeed,
VDAC1 is now accepted as a key player in mitochondria-
mediated apoptosis, with VDAC1 silencing or over-
expression affecting apoptosis induction [1, 23, 33, 118-
122]. Exogenous over-expression of VDAC from various
sources was found to induce apoptotic cell death regard-
less of cell type [113, 118-122]. VDAC1 over-expression-
induced cell death was prevented by RuR [122, 123], Bcl2,
DIDS [120] or by over-expression of HK-I [118, 122, 124],
with all these agents directly interacting with VDAC1. Final-
ly, reducing VDAC1 expression by siRNA efficiently pre-
vented cisplatin-induced apoptosis and Bax activation in
non-small cell lung cancer (NSCLC) cells [125], and inhibited
selenite-induced PTP opening in HeLa cells [126]. VDAC1-
siRNA also attenuated endostatin-induced apoptosis [127].
In addition to the evidence above, release of Cyto c via
purified VDAC reconstituted into Cyto c-encapsulating lipo-
somes has been demonstrated [36, 128, 129]. It is thus
proposed that VDAC1 oligomerization is a key step in the
release of the pro-apoptotic proteins from the IMS to the
cytosol [23, 28-31, 36, 104, 112, 113].
A VDAC1 oligomeric structure as a Cyto c release pathway
When considering models of VDAC1-mediated protein re-
lease, the molecular sizes of the released proteins (12 to
100 kDa) and the diameter of the VDAC1 pore (2.6-3.0 nm)
should be considered. The VDAC1 pore can allow passage
of nucleotides and small molecules but is too small for the
passage of a folded protein like Cyto c. As such, we pro-
posed the formation of a large protein-conducting channel
within a VDAC1 homo-oligomer serving as the Cyto c re-
lease route. Indeed, upon apoptosis induction by various
stimuli, VDAC1 undergoes conformational changes and
oligomerization, followed by Cyto c release, and finally,
apoptosis [29, 33, 36, 118, 129].
Apoptosis induction leads to VDAC1 oligomerization
regardless of the cell type or apoptosis inducer used, in-
cluding staurosporine (STS), curcumin, As2O3, etoposide,
cisplatin, selenite, H2O2 or UV light, all affecting mitochon-
dria yet acting via different mechanisms [28, 112]. Moreo-
ver, shifting the equilibrium towards the VDAC1 oligomeric
state upon over-expression of the protein in the absence of
apoptosis stimuli resulted in release of pro-apoptotic pro-
teins, leading to cell death, regardless of cell type, in a
manner that could be inhibited by anti-apoptotic proteins
[23, 33, 113, 118-122]. The specific lipid composition of the
OMM significantly enhances VDAC1 oligomerization [130],
while p53 also promotes VDAC1 oligomerization [131].
Several VDAC1-interacting molecules inhibit both apop-
tosis and VDAC1 oligomerization as induced by various
stimuli [28, 104, 112, 113, 119, 120, 122, 132, 133]. These
include 4,4 diisothiocyanostilbene-2,2-disulfonic acid
(DIDS), 4-acetamido-4-isothiocyanato-stilbene-2,2-
disulfonic acid (SITS), 4,4' diisothiocyanatodihy-
drostilbene-2,2'- -
dinitrostilbene--disulfonic acid (DNDS), and diphenyla-
mine-2-carboxylate (DPC). Similarly, the newly developed
VDAC1-interacting molecules AKOS-022 and VBIT-4 pre-
vented VDAC1 oligomerization and apoptosis as induced by
various means and in several cell lines [134]. These com-
pounds also protected against apoptosis-associated mito-
chondrial dysfunction, specifically restoring dissipated mi-
tochondrial membrane potential, and thus cell energy and
metabolism, decreasing ROS production, and preventing
disruption of intracellular Ca2+ levels. The use of these
apoptosis inhibitors thus supports the tight coupling be-
tween VDAC1 oligomerization and apoptosis induction.
Inhibiting apoptosis at an early stage via prevention of
VDAC1 oligomerization may be an effective approach for
blocking or slowing apoptosis in neurodegenerative disor-
ders [135, 136] and various cardiovascular diseases, where
enhanced apoptosis also occurs [137-139].
To conclude, it is proposed that VDAC1 exists in a dy-
namic equilibrium between the monomeric and oligomeric
states, with apoptosis inducers or VDAC1 over-expression
shifting the equilibrium towards oligomerization. Thus, the
cellular VDAC1 expression level and its oligomeric state are
crucial factors in the process of mitochondria-mediated
apoptosis.
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 19 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
The mode of action of apoptotic stimuli and VDAC1 over-
expression – a new concept
Several studies have demonstrated that the induction of
apoptosis by various reagents is accompanied by an in-
crease in the level of VDAC1 expression [54]. These include
arbutin (hydroquinone-O-beta-D-glucopyranoside), a tyro-
sinase inhibitor that induces apoptosis in A375 human ma-
lignant melanoma cell by causing VDAC1 over-expression
[140]. Up-regulation of VDAC1 expression was noted in
acute lymphoblastic leukemia (ALL) cell lines following
FIGURE 5: VDAC1 function in cell death, with apoptosis inducers enhancing VDAC1 expression levels and oligomerization. A schematic repre-
sentation of VDAC1 function in cell death - Different models for the release of apoptogenic proteins, such as Cyto c (purple) and AIF (yellow),
are shown. (A) Proposed model suggesting that apoptotic stimuli or conditions cause enhanced VDAC1 expression via increases in [Ca2+]i levels
or transcription factors, leading to activation of the VDAC1 promoter. The increase in VDAC1 expression shifts the equilibrium towards the
VDAC1 oligomeric state, forming a hydrophilic protein-conducting channel capable of mediating the release of apoptogenic proteins (e.g., Cyto
c and AIF) from the mitochondrial IMS to the cytosol. (B) Mitochondrial Ca2+ overload induces apoptosis. Ca2+ transport across the OMM, as
mediated by VDAC1, and then across the IMM, as mediated by the MCU, leads to Ca2+ overload in the matrix. This, in turn, causes dissipation of
the membrane potential, mitochondrial swelling, PTP opening, Cyto c/AIF release and the triggering of apoptotic cell death. (C) Bax/Bak oli-
gomerization and activation, forming a route for Cyto c/AIF release. (D) Bax activation leads to its association with the OMM, followed by its
oligomerization as a large oligomer/complex, forming a Cyto c/AIF-conducting channel. (E) The interaction of the pro-apoptotic protein Bax
with VDAC1 forms hetro-oligomers that mediate Cyto c/AIF release. (F) Prolonged VDAC1 closure leads to mitochondrial matrix swelling and
OMM rupture, resulting in the appearance of a non-specific release pathway for apoptogenic proteins.
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 20 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
prednisolone treatment [141]. Somatostatin up-regulated
the expression of VDAC1 and VDAC2 in the LNCaP prostate
cancer cell line [142]. Up-regulation of VDAC1 expression
levels was also induced by the hepatitis E virus ORF3 pro-
tein [143]. Also, both UV irradiation and ROS were shown
to up-regulate VDAC1 expression [144-146] that was pre-
vented by the ROS chelator epigallocatechin [144]. Cispla-
tin induced VDAC1 over-expression in a cisplatin-sensitive
cervix squamous cell carcinoma cell line (A431), while
down-regulation of VDAC1 was noted in a cisplatin-
resistant cell line (A431/Pt) [147]. Up-regulation of VDAC
expression was proposed to mediate the actions of vori-
nostat, a histone deacetylase inhibitor that induced syner-
gistic anti-proliferative and pro-apoptotic effects in NSCLC
cells in combination with EGFR-tyrosine kinase inhibitors
[148]. Finally, apoptosis induction by H2O2, etoposide, cis-
platin, selenite and UV irradiation all led to enhanced
VDAC1 expression levels, which was accompanied by
VDAC1 oligomerization, Cyto c release and apoptosis [54,
112, 113].
As apoptosis induction by agents such as STS, As2O3,
and selenite disrupt [Ca2+]i homeostasis and energy pro-
duction [112, 113, 149], apoptosis-induced VDAC1 up-
regulation is proposed to be mediated by an increase in
[Ca2+]i. Indeed, we have shown that pro-apoptotic-agents
induce cell death through Ca2+-dependent up-regulation
of VDAC1 expression levels [54, 112, 113]. Direct elevation
of [Ca2+]i by the Ca2+-mobilizing agents A23187, ionomycin
and thapsigargin also resulted in VDAC1 over-expression,
VDAC1 oligomerization and apoptosis [112, 113]. In con-
trast, decreasing [Ca2+]i using the cell-permeable Ca2+-
chelating reagent BAPTA-AM inhibited VDAC1 over-
expression, VDAC1 oligomerization and apoptosis. Thus,
the increase in [Ca2+]i induced by apoptosis stimuli was
found to be a pre-requisite for induction of VDAC1 over-
expression and apoptosis [112, 113]. The over-expressed
VDAC1 forms oligomers and this triggers Cyto c release and
then cell death. The following new concept of apoptosis
induction is thus proposed [112, 113]: Apoptosis inducers
increased [Ca2+]i enhanced VDAC1 expression levels
VDAC1 oligomerization Cyto c release apoptosis.
As such, up-regulation of the expression of VDAC1 may
represent a new common mode of action of apoptosis in-
duction.
VDAC1 AND CA2+ HOMEOSTASIS
Mitochondria serve as a major hub for cellular Ca2+ homeo-
stasis, regulating oxidative phosphorylation and modulat-
ing cytosolic Ca2+ signals of cell death and secretion [150,
151]. Mitochondria can rapidly sequester large amounts of
Ca2+ at the expense of the membrane potential across the
IMM and mediate Ca2+ efflux. Ca2+ is an essential co-factor
for several rate-limiting TCA enzymes (i.e., pyruvate dehy-
drogenase, isocitrate dehydrogenase, and -ketoglutarate
dehydrogenase) located in the matrix, such that intra-
mitochondrial Ca2+ controls energy and metabolism. To
reach the matrix, Ca2+ must cross both the OMM and the
IMM, in a manner mediated by several proteins. VDAC1
acts in the OMM, whereas the mitochondrial Ca2+ uni-
porter (MCU) [152, 153] and the Na+/Ca2+ exchanger, NCLX,
the major Ca2+ efflux mediator [154], are both found in the
IMM.
The function of VDAC1 in regulation of cell Ca2+ homeo-
stasis was recently summarized [155]. VDAC1 in the OMM
is highly Ca2+-permeable and transports Ca2+ into and out
of the IMS [156-159], consequently allowing Ca2+ access to
IMM transporters. Ruthenium red (RuR) [157, 160, 161],
ruthenium amine binuclear complex (Ru360) [161], the
photo-reactive analogue azido ruthenium (AzRu) [162] and
the lanthanides La3+and Tb3+ [160] all reduce VDAC1 con-
ductance in the case of native but not mutated VDAC1 [160,
161].
Competition between Ca2+ and RuR [160] suggests that
VDAC1 possesses divalent cation-binding site(s). The physi-
ological function of the VDAC1 Ca2+-binding site(s), reflect-
ed in the regulation of VDAC1 gating by physiological levels
of Ca2+, prolongs a fully open state of the channel, thereby
promoting metabolite exchange [156]. Thus, it has become
apparent that VDAC1 both mediates Ca2+ transport and is
also regulated by Ca2+ binding.
VDAC1 also functions in the ER/mitochondria-Ca2+
cross-talk. VDAC1 is a constituent of a supra-molecular
complex composed of the IP3 receptor in the ER and
VDAC1 in the OMM, linked by a chaperone called GRP75
[13, 163], together with mitofusin-2 [164, 165].
Thus, by transporting Ca2+, VDAC1 plays a fundamental
role in regulating mitochondrial Ca2+ homeostasis, oxida-
tive phosphorylation, and Ca2+ crosstalk among mitochon-
dria, cytoplasm, and the ER.
VDAC AND OXIDATIVE STRESS
Oxidative stress results when production of ROS exceeds
the capacity of mitochondrial and cellular anti-oxidant de-
fenses to remove these toxic species. ROS act as second
messengers in cell signaling and are essential for multiple
biological processes in normal cells. However, ROS are also
well known contributors to cell proliferation and cell death
[166-169], provoking damage to multiple cellular orga-
nelles and processes [170].
Mitochondria are the major source of ROS formation,
mostly at complex I (site IQ), complex II (site IIF) and com-
plex III (site IIIQo) [171-173]. O2- generated at complex III
is released to the cytosol through VDAC1. By contrast, O2-
produced at complexes I and II is released to the matrix,
where it is rapidly converted to H2O2 by superoxide dis-
mutases located in the mitochondrial matrix (MnSOD or
SOD2) and the cytosol (Cu,ZnSOD or SOD1) [174]. H2O2 acts
as a cell signaling molecule that does not disrupt redox
homeostasis [175] and modulates the pro-survival
PI3K/Akt/mTOR HIF-1 and MAP/ERK pathways to promote
tumorigenesis and metastasis [176-178]. H2O2 also forms
reaction. Whereas both H2O2 and O2- react with mito-
chondrial and extra-
reactive that its effects are almost completely restricted to
mitochondria. O2-
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 21 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
proteins, and damage mitochondrial DNA and lipids in the
MIM [179, 180]. Cytosolic ROS also activate members of
the MAPK family of serine/threonine kinases, especially the
c-Jun N-terminal kinase (JNK), the extracellular signal-
regulated kinase (ERK 1/2), and p38, whose signaling can
cause mitochondrial dysfunction. JNK translocation to mi-
tochondria has been shown to cause mitochondrial dys-
function in several models [181, 182].
Cells possess several anti-oxidant defense mechanisms,
including the presence of various endogenous molecules,
such as glutathione [183-187], or the expression of en-
zymes like superoxide dismutases (SOD1 and SOD2), cata-
lase, and peroxidase [188]. About 1% of ROS escape elimi-
nation and can be released to the cytosol by crossing the
OMM, where they can attack and modify DNA, lipids and
proteins affecting cell survival [189].
VDAC1 has been proposed to mediate ROS release
from the IMS to the cytosol. This is based on the finding
that ROS release from mitochondria was decreased when
HK-I and HK-II bound to VDAC1 were over-expressed in
HEK cells, reducing intracellular ROS levels [190-192] and
protecting against oxidant-induced cell death [190, 193]. In
tumor cells, VDAC opening or closing increases or decreas-
es OXPHOS and subsequently increases or decreases ROS
generation, respectively. Erastin, a small molecule that
antagonizes the inhibitory effect of tubulin on VDAC, in-
creases mitochondrial ].
Thus, blockage of tubulin-dependent VDAC inhibition
works as a pro-oxidant anti-Warburg metabolic switch to
promote cancer cell death [88, 194]. By contrast, VDAC1
closure by DIDS and dextran sulfate inhibits the efflux of
O2- -state level of
O2-, sensitizing mitochondria to Ca2+-induced MPT [195].
Cysteine residues, often involved in redox reactions,
metal coordination and thiol-disulfide interchanges, are
extremely vulnerable to oxidation by ROS. VDAC has been
proposed to function in physiological redox regulation via
the modification of the sulfhydryl groups of VDAC [196]. In
humans, VDAC1 contains two cysteines, VDAC2 contains
nine cysteines and VDAC3 contains six cysteines, all of
which are predicted to protrude towards the IMS and can
be subjected to oxidation by ROS [4]. We have shown that
for VDAC1, deletion of both cysteines does not affect
channel conductance, VDAC1 oligomerization or apoptosis
[53]. Cysteines contribute to the folding, function and sta-
bility of hVDAC2. VDAC3 was found to be the target of mi-
tochondrial ROS specifically generated by complex III and
was proposed to act as a sensor of the oxidative state of
the IMS via cysteine residue modification [197].
Accumulating evidence indicates that ROS play a key
role in Cyto c release from mitochondria and that this in-
volves VDAC1. Apoptosis-inducing agents, such as inorgan-
ic arsenic compounds [198, 199] and doxorubicin [200],
induce apoptosis by inducing ROS generation. The inhibi-
tion of O2--induced apoptosis by DIDS, an inhibitor of
VDAC channel activity, or by anti-VDAC1 antibodies [12,
129, 201], suggests that O2- c release via
VDAC1-dependent permeabilization of the OMM [129].
Moreover, O2- c release in
VDAC1-reconstituted liposomes [129]. In other studies, it
was found that ROS-induced alterations of VDAC1 and/or
ANT could make the PTP selective for Cyto c release, with-
out causing further mitochondrial damage [129, 202].
Moreover, it was shown that ROS induced up-regulation of
VDAC1 that could be prevented by the ROS chelator, epi-
gallocatechin [144]. It has been suggested that ROS-
mediated Cyto c and SOD1 release from mitochondria in-
volves VDAC, leading to increased susceptibility of mito-
chondria to oxidative stress and apoptosis [203].
VDAC is also affected by hypoxic conditions shown to
induce cleavage at the C-terminal end of the protein
(VDAC1-C), with such cleavage being prevented upon
silencing of HIF-1 expression [204, 205]. It was proposed
that hypoxia, by inducing formation of VDAC1-
selective protection from apoptosis that allows mainte-
nance of ATP and cell survival in hypoxia [206].
VDAC1 AS A HUB PROTEIN – MODULATION OF VDAC1-
MEDIATED APOPTOSIS AND METABOLISM VIA
INTERACTING PROTEINS
As presented above, VDAC1 is crucial for many cellular
processes, including metabolism, Ca2+ homeostasis, apop-
tosis, and other activities regulated via the interaction of
VDAC1 with many proteins associated with cell survival and
cellular death pathways [1, 29-31]. Indeed, VDAC1 is con-
sidered as a hub protein, interacting with over 100 proteins
that regulate the integration of mitochondrial functions
with other cellular activities [207]. VDAC1 serves as an an-
chor protein for diverse sets of cytosolic, ER, and mito-
chondrial proteins [12, 208] that together regulate meta-
bolic and signaling pathways, provide energy for cellular
functions, or trigger cell death. Thus, VDAC1 appears to be
a convergence point for a variety of cell survival and death
signals, mediated via association with ligands and proteins.
In support of this viewpoint, the conserved nature of
VDAC1 [1] is in agreement with the finding that hub pro-
teins are more evolutionarily conserved than are non-hub
proteins [209]. VDAC1 protein-protein interaction (PPI)
networks contain both hub-bottlenecks [210] (namely
nodes with high degree values constituting vulnerable are-
as of the network) and/or bottlenecks (those with high
intersecting nodes [211]). The VDAC1 interactome includes
proteins involved in metabolism, apoptosis, signal trans-
duction, anti-oxidation, and DNA- and RNA-associated pro-
teins and more (Supplemental Table S1) [1, 29, 31, 32].
Furthermore, these proteins may be located in the OMM,
IMM, the IMS, the cytosol, ER, plasma membrane, and
nucleus. Importantly, we have been able to develop
VDAC1-based peptides which can interfere with these in-
teractions, leading to impaired cell metabolism and apop-
tosis [25-27, 212, 213].
Interactions of VDAC1 with metabolism-related proteins
VDAC1 displays binding sites for a large number of metabo-
lism-related proteins, such as glycerol kinase (GK), HK, c-Raf
kinase, ANT, tubulin, [1, 29-31] and the glycolytic enzyme
GAPDH (glyceraldehyde 3-phosphate dehydrogenase) [214].
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 22 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
Mitochondrial creatine kinase (MtCK), in its octameric state,
interacts with VDAC1 [35] and causes decreased affinity of
VDAC1 for HK and Bax [215] (Supplemental Table S1). HK bind-
ing to VDAC1 [25, 104, 118, 122, 124, 216] allows direct cou-
pling of mitochondrially generated ATP to glucose phosphory-
lation. Thus, the formation of a VDAC1-HK complex coordi-
nates glycolytic flux with the actions of the TCA cycle and ATP
synthase [1, 33, 81].
The OMM protein CPT1a that catalyzes the primary step of
fatty acid oxidation interacts with VDAC1 [65]. Another OMM
protein interacting with VDAC1 is the TSPO, involved in the
transport of cholesterol into mitochondria [217]. Aldolase,
involved in gluconeogenesis and glycolysis, was also shown to
interact with VDAC1 [17].
Interactions of VDAC1 with apoptosis-related proteins
The Bcl-2 family comprises pro-apoptotic (e.g. Bid, Bax, Bim
and Bak) and anti-apoptotic (e.g. Bcl-2 and Bcl-xL) members
that up- or down-regulate apoptosis, respectively [218, 219].
VDAC1 function in apoptosis can be regulated by interactions
with anti-apoptotic proteins, such as Bcl2 and Bcl-xL [23, 25,
26, 117, 220-223], resulting in inhibition of apoptotic path-
ways. Bcl-2 and Bcl-xL were shown to interact with bilayer-
reconstituted VDAC1 and subsequently to reduce the channel
conductance of native but not mutated VDAC1, as well as to
protect against apoptosis in cells expressing native but not
mutated VDAC1 [25, 26]. The VDAC1 domains that interact
with Bcl-2 and Bcl-xL to confer anti-apoptotic activity were
identified by site-directed mutagenesis [25]. Mcl-1 has been
shown to directly interact with VDAC to increase mitochondri-
al Ca2+ uptake and ROS generation [224]. The HK-VDAC inter-
action also prevents release of pro-apoptotic factors, such as
Cyto c, and subsequent apoptosis. Thus, HK plays a role in
tumor cell survival via inhibition of apoptosis [118]. The inter-
action between TSPO and VDAC is considered to play a role in
the activation of the mitochondrial apoptosis pathway, given
the reported grouping of TSPO molecules around VDAC, po-
tentially reflecting TSPO polymerization [225], and the in-
creased ROS generation by TSPO in the proximity of VDAC,
leading to apoptosis induction [225, 226]. Nek1 (NIMA-related
protein kinase 1) phosphorylates VDAC1 on serine 193, with
this leading to apoptosis inhibition [146, 227]. Finally, the pro-
apoptotic protein BNIP3 was shown to interact with VDAC so
as to induce mitochondrial release of endonuclease G [228].
Interactions of VDAC1 with cytoskeletal proteins
VDAC1 interacts with several cytoskeletal proteins, such as
gelsolin (Gsn), with this interaction resulting in inhibited
VDAC1 channel activity and Cyto c release from liposomes
through direct binding to VDAC1 in a Ca2+-dependent manner
[229, 230]. Tubulin was shown to associate with VDAC1 [231]
and induce VDAC1 closure [86], proposed to sustain the War-
burg effect [232]. It was further proposed that tubulin, VDAC1,
and MtCK form a super-complex that is structurally and func-
tionally coupled to the ATP synthasome [233]. G-actin directly
and selectively binds to VDAC in yeast, [234], reducing con-
ductance of the Neurospora crassa VDAC channel [235]. Mi-
crotubule-associated protein 2 (MAP2) was shown to bind
VDAC [236]. The interaction of VDAC1 with Tctex-1/DYNLT1
(dynein light chain) was also demonstrated [237].
Interactions of VDAC1 with signaling proteins
Superoxide dismutase 1 (SOD1) is a predominantly cytosolic
protein, with mutant SOD1 being present mostly in fractions
enriched for mitochondria [238-240]. Mutant SOD1 associated
with amyotrophic lateral sclerosis (ALS) bound to bilayer-
reconstituted VDAC1 and inhibited its channel conductance
[241]. Mutant SOD1 also interacted with Bcl2 protein and
altered the interaction between Bcl-2 and VDAC1, thus reduc-
ing OMM permeability [242].
Endothelial NO synthase (eNOS) was also found to bind
VDAC1. Such interactions amplified eNOS activity in an intra-
cellular Ca2+-mediated manner [243]. These findings suggest
that the interaction between VDAC and eNOS may be im-
portant for regulating eNOS activity and modulation of VDAC
[243].
The mitochondrial anti-viral signaling protein MAVS, also
known as IPS-1, VISA, or Cardif [244], and localized in the
OMM, was demonstrated to mediate its pro-apoptotic activity
via VDAC1 and to modulate VDAC1 protein stability via the
ubiquitin-proteasome pathway [245]. VDAC was further pro-
posed to interact with the L-type Ca2+ channel [246].
Several additional proteins were shown or proposed to di-
rectly interact with VDAC1 (Supplemental Table S1). These
include PBP74, also known as mtHSP70/GRP75/mortalin [237],
- -synuclein [248]. VDAC1-
interacting protein complexes mediate and/or regulate meta-
bolic, apoptotic, and other processes that may be impaired in
disease.
VDAC INVOLVEMENT IN DISEASE
Mitochondria occupy a central position in cell life and
death and mitochondrial dysfunction has been implicated
(AD), Parkinson's disease (PD), amyotrophic lateral sclero-
sis (ALS), diabetes, and cardiovascular diseases (CVDs).
VDAC1 functions as mitochondria gatekeeper that regu-
lates ATP production, Ca2+ homeostasis and apoptosis exe-
cution, all indispensable for proper mitochondrial function,
and consequently, for cell normal physiology. Thus, the
association of VDAC with various diseases is not surprising.
Furthermore, VDAC over-expression is a common feature
of cancer, AD, type 2 diabetes (T2D) and CVDs. The over-
expression of VDAC1 in cancer [54, 59], in affected regions
of AD brains [97- -cells of T2D [101] and in CVDs
[250], is a feature common to these diseases. As VDAC1
over-expression induces apoptotic cell death [58, 113, 119,
120, 122], its over-expression in CVDs, AD and T2D, may be
a common mechanism in these pathologies.
The cancer-mitochondria-metabolism-apoptosis-VDAC1 link
Cancer is a complex disease in which cells acquire a common
set of properties, including unlimited proliferation, metabolic
reprograming, and resistance to anti-proliferative and apop-
totic cues [78, 250]. Emerging evidence indicates that meta-
bolic reprogramming, which supports macromolecule synthe-
sis, bioenergetics demands, and cellular survival is a character-
istic of nearly all cancers [68, 251]. Over the years, Otto War-
burg's view of cancer as a metabolic disease was gradually
displaced with the view of cancer as a genetic disease [252].
Today, however, cancer is again being seen as a metabolic
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 23 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
disease, primarily associated with impaired mitochondrial
function and metabolism [75, 79].
VDAC1 is highly expressed in different tumors [54, 59],
contributing to their metabolism via the transport of various
metabolites, and the binding and channeling of mitochondrial
ATP directly to HK [5]. This results in mitochondria regulating
glycolytic flux with that actions of the TCA cycle and ATP syn-
thase to fulfill the requirements of tumors for metabolites or
metabolite precursors. Indeed, tumors switch their HK expres-
sion pattern predominantly to present the VDAC1-binding
isoforms (HK-I, HK-II) [253]. The requirement of cancer cells
for VDAC1 is demonstrated by down-regulation of VDAC1,
resulting in reduced metabolite exchange between mitochon-
dria and cytosol and inhibition of cell and tumor growth [32,
58, 59, 90, 91].
VDAC1 also regulates apoptosis in cancer cells by interact-
ing with the anti-apoptotic proteins Bcl-2 and Bcl-xL [23, 25,
26, 254] and HK [23, 27], interactions that protect tumor cells
from cell death [23, 27]. Thus, activating mitochondria-
mediated apoptosis directly or via generating stress responses
[255-257] is a strategy to treat cancer. Indeed, a large number
of anti-cancer chemotherapeutic agents exert their therapeu-
tic action by inducing apoptosis of malignant cells [258-263],
mainly by activating the Cyto c/caspase-9 pathway. These
include etoposide, doxorubicin, lonidamine, betulinic acid,
arsenite, CD437, and several amphiphilic -helical
peptides [264]. Therefore, targeted activation of apoptosis in
cancerous tissues may be exploited as a potential route to
cancer therapy [265]. However, they do not act on cancer
stem cells (CSCs), which are resistant to chemo- and radio-
therapies [266-268]. The CSC hypothesis postulates that a sub-
population of malignant cells constantly supply the tumor with
cancerous cells. CSCs, as embryonic and somatic stem cells,
have self-renewal and multi-potent differentiation abilities
[269, 270]. Recent studies from the Shoshan-Barmatz group
[91, 213] have demonstrated novel strategies for eliminating
CSCs.
Regulation of VDAC1 expression by miRNA was demon-
strated in several studies. In serum-starved cervical cancer
cells, miR320a promoted mitophagy [93], while ectopic over-
expression of miR320a blocked tumor cell proliferation and
invasion in NSCLC, both in vitro and in vivo [271]. Another
miRNA species, miR-7, was shown to inhibit VDAC1 expression,
proliferation and metastasis in hepatocellular carcinoma [94],
possibly by affecting the PTP [95].
Thus, the importance of VDAC1 for cancer cell survival is
clearly reflected in the above findings, with silencing VDAC1
expression in cancer cells resulting in a multi-pronged attack
on cancer hallmarks.
Neurodegenerative diseases, mitochondria, apoptosis, and
VDAC
There is emerging evidence connecting mitochondrial dysfunc-
tion to neurodegenerative disorders [169
disease (HD), ALS and AD, impaired mitochondrial function has
been reported [272], with a focus on the involvement of mito-
chondria-mediated apoptotic death [273]. Mitochondrial dys-
function was proposed as an early event in AD pathogenesis,
as reflected in reduced metabolism, increased ROS, lipid pe-
roxidation and disruption of Ca2+-homeostasis, [274-276].
Moreover, mitochondria-mediated apoptosis is common to
neurological disorders in which premature neuron death is
implicated [273, 277, 278], with caspases playing dominant
roles [279-281 s mitochondrial
respiration [282] and activates Cyto c release, thereby pro-
moting apoptosis [283].
Several studies suggested that VDAC malfunction is asso-
ciated with AD [284-287], Down's syndrome [287], and familial
ALS [241, 288]. High levels of VDAC1 were demonstrated in
-mortem brains
of AD patients and in amyloid precursor protein (APP) trans-
-VDAC interactions are toxic to AD-
affected neurons [97, 98, 286, 287, 289-291]. The expression
of hVDAC-2 was shown to be associated with neurodegenera-
tive diseases, including ALS [288], epilepsy [292], and AD [286].
As VDAC1 over-expression was shown to lead to apoptotic
cell death [58, 113, 119, 120, 122] and high-levels of VDAC1
post-mortem brains and APP transgenic mice [97-99], we pro-
pose that over-expressed VDAC is associated with neuronal
cell death [291].
We have demonst
VDAC1, specifically with the VDAC1 N-terminal region and that
-
e-
ing prevented in cells depleted of VDAC1 by siRNA [291].
VDAC was also shown to interact with phosphorylated Tau,
leading to mitochondrial dysfunction [290]. In addition, an
increase in nitrated VDAC1 levels in AD was reported, reflect-
ing oxidative damage to VDAC [293], and possibly affecting cell
energy and metabolite homeostasis [284]. The involvement of
plasmalemmal VDAC in AD was also proposed [285, 289].
The relationship between VDAC1 expression levels and
neurodegenerative disorders is also reflected in the finding
that in patients and animal models of several neurodegenera-
tive disorders, such as AD, HD, and spinocerebellar ataxias,
miR-29a expression levels were reduced [294]. miR-29a was
also shown to regulate cell survival of astrocytes differentially
by targeting VDAC1 [295]. These findings suggest that VDAC1
down-regulation by miR-29 is an important aspect of neuronal
cell survival in the brain [294]. As VDAC1 over-expression trig-
gers apoptosis [120-122], and high-levels of VDAC1 were
demonstrated in AD post-mortem brains and in AD-like trans-
genic mice [99], the reported decrease in miR-29a in AD [294]
may be associated with neuronal cell death. Indeed, miR-
320a-mediated down-regulation of VDAC1 expression has
been proposed as a novel therapeutic target for astroglia-
mediated HIV-1 neuropathogenesis [296].
Finally, several proteins interacting with VDAC, such as
-synuclein and ApoE, were proposed to be involved in
several neurodegenerative diseases, affecting intraneuronal
Ca2+ [155]. These findings point to VDAC1 as a potential target
for novel therapeutic strategies for neurodegenerative diseas-
es.
T2D, metabolism, mitochondria and VDAC1
T2D is the most common metabolic disease [297]. Defective
insulin secretion, insulin resistance at target tissues and a loss
of funct -cells contribute to T2D, and dysregulation of
glucose homeostasis [298]. Recently, it has been shown that
hyperglycemia increases VDAC1 expression in pancr -
cells [101] and in the kidney [102]. VDAC1 levels were in-
creased in mouse coronary vascular endothelial cells (MCECs)
isolated from diabetic mice. This was associated with in-
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 24 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
creased [Ca2+]m, O2 production, and PTP opening activity [299].
Down-regulation of VDAC1 in diabetic MCECs decreased
[Ca2+]m and subsequently affected PTP activity and ROS pro-
duction [300]. As glucose-stimulated insulin secretion depends
on the generation of ATP and other metabolites in the mito-
chondria [301], and VDAC1 regulates energy and metabolism,
VDAC1 is thus required for insulin secretion. Recently, lncRNA-
H19/miR-675 was reported to regulate high glucose-induced
apoptosis by targeting VDAC1, and thus provides a novel ther-
apeutic strategy for the treatment of diabetic cardiomyopathy
[96]. These findings point to the connection between VDAC,
mitochondrial function and the pathogenesis of T2D.
Cardiovascular diseases, mitochondria, apoptosis and VDAC
It is known that most CVDs evolve into heart failure and that
the loss of cardiac myocytes plays a critical role in the patho-
genesis of CVDs. Activation of mitochondria-mediated apopto-
sis has been implicated in ischemia/reperfusion injury [302].
VDAC levels were increased in cardiomyoblast H9c2 cells [249].
As VDAC1 over-expression is associated with apoptosis [58,
113, 119, 120, 122], it is possible that increased cardiomyo-
cyte susceptibility to mitochondrial-mediated cell death is
related to the increase in VDAC1 levels. Indeed, the effect of
resveratrol against myocardial ischemia/reperfusion injury
showed involvement of VDAC1 down-regulation [100].
The findings presented above suggest that modulating
VDAC1 expression levels or its apoptotic activity are possible
strategies to either activate apoptosis in cancer or inhibit
apoptosis in CVDs, AD and T2D.
UNRAVELING VDAC1-BASED THERAPIES
VDAC1-based strategies are expected to be effective in
various diseases characterized by altered cell metabolism
and/or apoptosis and by VDAC1 over-expression. As VDAC1
over-expression induces apoptotic cell death [58, 113, 119,
120, 122], we suggest that this may be a common mecha-
nism in the pathology of CVDs, AD and T2D. Modulating
VDAC1 expression levels or its apoptotic activity are possi-
ble strategies to either activate apoptosis in cancer or in-
hibit apoptosis in CVDs, AD and T2D. In this review, VDAC1-
based therapeutic strategies targeting tumor cells are pre-
sented. These cancer therapy strategies include siRNA al-
tering the normal functioning of cancer cells, leading to
growth arrest, and VDAC1-based peptides that impair en-
ergy homeostasis and minimize the self-defense mecha-
nisms of these cells, and that can be used to overcome
protective and pro-survival actions taken by cancer cells.
VDAC1-depletion using RNAi
Specifically targeting metabolism in cancer cells presents a
potential therapeutic strategy. However, although glucose
metabolism is increased in cancer cells, these cells mostly use
the same glycolytic enzymes as do normal cells, so that the
choice of glycolytic enzymes as targets for cancer treatment
may increase the risk of adverse and undesirable consequenc-
es [303n-
drial function, regulating cellular energy and metabolism, and
over-expressed in cancer, offers a unique target for anti-
cancer therapies. Down-regulation of VDAC1 addresses the
cancer trademark of cell metabolic and energy reprogramming,
leading to disrupted cancer cell energy and metabolism ho-
meostasis.
VDAC1 depletion using specific siRNA (si-VDAC1) led to re-
duced cellular ATP levels and inhibited cell and tumor growth
in cervical and lung cancers [58, 59, 90]. Using a sub-
cutaneous and intracranial-orthotopic GBM model, we found
that VDAC1 depletion resulted in inhibited tumor growth, with
the residual tumor showing reversed oncogenic properties,
including metabolic reprograming and inhibited proliferation,
angiogenesis, EMT, invasiveness and stemness, leading to
differentiation into neuron- and astrocyte-like cells [91] (Fig.
4).
VDAC1-based peptides as potential anti-cancer therapy
A hallmark of cancer cells is their ability to suppress pro-
apoptotic pathways and/or to activate anti-apoptotic mecha-
nisms [78, 250] associated with drug resistance [304], such as
the Bcl-2 family of proteins and HK, preventing the release of
Cyto c from mitochondria. Since the anti-apoptotic proteins
HK-I, HK-II, Bcl2 and Bcl-xL have been found to be expressed at
high levels in many types of cancer [81, 253, 305-310] and
interact with VDAC1 [1, 22, 23-27, 81, 82, 84, 118, 122, 124,
128, 220, 311, 312], the interaction of VDAC1with these pro-
teins is proposed as an appropriate target to induce apoptosis.
We have engineered VDAC1-based peptides that interfere
with the activity of the pro-survival proteins Bcl-2, Bcl-xL and
HK [23, 25-27, 118, 122, 212]. Via point mutations, VDAC1
domains and amino acid residues important for interactions
with HK, Bcl-2 and Bcl-xL were identified and cell-penetrating
VDAC1-based peptides targeting these interactions were de-
signed and tested [23, 25-27, 118, 122]. These VDAC1-based
peptides were found to induce cancer cell death in a panel of
genetically characterized cancer cell lines, regardless of cancer
type or mutation status, with perceived specificity toward
cancerous cells [23, 27, 212]. Studies demonstrated a triple
mode of action, namely energy and metabolism impairment,
interference with the action of anti-apoptotic proteins, and a
triggering of cell death.
In an ex vivo study, cell-penetrating VDAC1-based peptides
were found to induce apoptotic cell death in the cancerous B-
cells of peripheral blood mononuclear cells obtained from
chronic lymphocytic leukemia (CLL) patients, yet spared those
obtained from healthy donors, pointing to the potential of
VDAC1-based peptides as an innovative and effective anti-CLL
therapy.
In a GBM mouse model, i.v.-administered VDAC1-based
peptide Tf-D-LP4 crossed the blood-brain barrier and was
found to inhibit tumor growth by inducing apoptosis and over-
expression of apoptotic proteins [213]. Such treatment simul-
taneously attacked several cancer hallmarks, causing impair-
ment of energy and metabolic homeostasis, inhibition of tu-
mor growth and induction of apoptosis. VDAC1-based pep-
tides, expecting to also affect other cancers, provide the op-
portunity for the development of new anti-cancer therapies
that will allow overcoming the chemo-resistance of cancer
cells.
In summary, VDAC1 functions in ATP production and me-
tabolism, Ca2+ homeostasis and apoptosis execution are indis-
pensable for proper mitochondrial function of cancer cell, and
consequently, for cell activity. These VDAC-mediated activities
are regulated via interactions of VDAC1 with many proteins
that are critically involved in the regulation of cell survival and
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 25 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
cellular death pathways. VDAC1, standing at the crossroads
between mitochondrial-mediated energy and metabolism and
apoptosis, is a potential target for treating cancer and other
diseases involving dysregulated metabolism and/or apoptosis
and where VDAC1 is over-expressed. Thus, a new generation
of VDAC1-based therapeutics may impact the treatment of a
variety of diseases.
To conclude, the dysregulated cell stress response involves
mitochondria dysfunction and this play a critical role in tumor-
cardiovascular disease and type 2 diabetes. The role of VDAC1
in Ca2+ homeostasis, energy production and oxidative stress,
and with VDAC1 serving as a hub protein interacting with over
100 proteins allow it to mediate and regulate the integration
of mitochondrial functions with cellular activities. Thus, VDAC1,
standing at the crossroads between mitochondrial metabolite
transport, apoptosis and other cell stress-associated processes,
serves as the mitochondrial gatekeeper. This, together with its
over-expression in cancer and other diseases, including Alz-
diabetes, involves VDAC1 in the cell stress response and thus
represents a target to modulate the biology of cancer and
other diseases.
ACKNOWLEDGMENTS
This research was supported by grants from the Israel Science
Foundation (307/13), by Ezra and Yafa Yeruham and Sima and
Philip Needleman research funds to VSB, and R01CA184456
(NCI), COBRE Project GM103542 and ACS 13-041-01-IRG fund-
ing to ENM.
SUPPLEMENTAL MATERIAL
All supplemental data for this article are available online at
www.cell-stress.com.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
COPYRIGHT
© 2017 Shoshan-Barmatz et al. This is an open-access arti-
cle released under the terms of the Creative Commons
Attribution (CC BY) license, which allows the unrestricted
use, distribution, and reproduction in any medium, provid-
ed the original author and source are acknowledged.
Please cite this article as: Varda Shoshan-Barmatz, Eduardo N.
Maldonado and Yakov Krelin (2017). VDAC1 at the crossroads of
cell metabolism, apoptosis and cell stress. Cell Stress 1(1): 11-36.
doi: 10.15698/cst2017.10.104
REFERENCES
1. Shoshan-Barmatz V, De Pinto V, Zweckstetter M, Raviv Z, Keinan N,
Arbel N (2010). VDAC, a multi-functional mitochondrial protein regu-
lating cell life and death. Mol Aspects Med 31(3): 227-285. doi:
10.1016/j.mam.2010.03.002
2. Messina A, Reina S, Guarino F, De Pinto V (2012). VDAC isoforms in
mammals. Biochim Biophys Acta 1818(6): 1466-1476. doi:
10.1016/j.bbamem.2011.10.005
3. De Pinto V, Guarino F, Guarnera A, Messina A, Reina S, Tomasello
FM,Palermo V, Mazzoni C (2010). Characterization of human VDAC
isoforms: a peculiar function for VDAC3? Biochim Biophys Acta
1797(6-7): 1268-1275. doi: 10.1016/j.bbabio.2010.01.031
4.De Pinto V, Reina S, Gupta A, Messina A, Mahalakshmi R (2016).
Role of cysteines in mammalian VDAC isoforms' function. Biochim
Biophys Acta 1857(8):1219-1227. doi: 10.1016/j.bbabio.2016.02.020
5. Cheng EH, Sheiko TV, Fisher JK, Craigen WJ, Korsmeyer SJ (2003).
VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science
301 (5632): 513-517. doi: 10.1126/science.1083995
6. Raghavan A, Sheiko T, Graham BH, Craigen WJ (2012). Voltage-
dependant anion channels: novel insights into isoform function
through genetic models. Biochim Biophys Acta 1818(6): 1477-1485.
doi: 10.1016/j.bbamem .
7.Wu S, Sampson MJ, Decker WK, Craigen WJ (1999). Each mammali-
an mitochondrial outer membrane porin protein is dispensable: ef-
fects on cellular respiration. Biochim Biophys Acta 1452(1): 68-78.
doi: 10.1016/S0167-4889(99)00120-2
8. Sampson MJ, Decker WK, Beaudet AL, Ruitenbeek W, Armstrong D,
Hicks MJ, Craigen WJ (2001). Immotile sperm and infertility in mice
lacking mitochondrial voltage-dependent anion channel type 3. J Biol
Chem 276(42): 39206-39212. doi: 10.1074/jbc.M104724200
9. Weeber EJ, Levy M, Sampson MJ, Anflous K, Armstrong DL, Brown
SE, Sweatt JD, Craigen WJ (2002). The role of mitochondrial porins and
the permeability transition pore in learning and synaptic plasticity. J
Biol Chem 277(21): 18891-18897. doi: 10.1074/jbc.M201649200
10. Bathori G, Parolini I, Szabo I, Tombola F, Messina A, Oliva M, Sar-
giacomo M, De Pinto V, Zoratti M (2000). Extramitochondrial porin:
facts and hypotheses. J Bioenerg Biomembr 32(1): 79-89. doi:
doi:10.1023/A:1005516513313
11.Bathori G, Parolini I, Tombola F, Szabo I, Messina A, Oliva M, De
Pinto V, Lisanti M, Sargiacomo M, Zoratti M (1999). Porin is present in
the plasma membrane where it is concentrated in caveolae and
caveolae-related domains. J Biol Chem 274(42): 29607-29612. doi.:
10.1074/jbc.274.42.29607
12. Shoshan-Barmatz V, Hadad N, Feng W, Shafir I, Orr I, Varsanyi M,
Heilmeyer LM (1996). VDAC/porin is present in sarcoplasmic reticulum
from skeletal muscle. FEBS Lett 386(2-3): 205-210. doi: 10.1016/0014-
5793(96)00442-5
13. Shoshan-Barmatz V, Zalk R, Gincel D, Vardi N (2004). Subcellular
localization of VDAC in mitochondria and ER in the cerebellum. Bio-
chim Biophys Acta 1657(2-3): 105-114. doi:
10.1016/j.bbabio.2004.02.009
14. Sabirov RZ, Merzlyak PG (2012). Plasmalemmal VDAC controver-
sies and maxi-anion channel puzzle. Biochim Biophys Acta 1818(6):
1570-1580. doi: 10.1016/j.bbamem.2011.09.024
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 26 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
5. Buettner R, Papoutsoglou G, Scemes E, Spray DC, Dermietzel R
(2000). Evidence for secretory pathway localization of a voltage-
dependent anion channel isoform. Proc Natl Acad Sci U S A 97(7):
3201-3206. doi: 10.1073/pnas.060242297
16. Thinnes FP, Gotz H, Kayser H, Benz R, Schmidt WE, Kratzin HD,
Hilschmann N (1989). Identification of human porins. I. Purification of
a porin from human B-lymphocytes (Porin 31HL) and the topochemi-
cal proof of its expression on the plasmalemma of the progenitor cell.
Biol Chem Hoppe Seyler 370(12): 1253-1264. PMID: 2559744
17. Shoshan-BarmatzV, Israelson A (2005). The voltage-dependent
anion channel in endoplasmic/sarcoplasmic reticulum: characteriza-
tion, modulation and possible function. J Membr Biol 204(2): 57-66.
doi: 10.1007/s00232-005-0749-4
18. Bayrhuber M, Meins T, Habeck M, Becker S, Giller K, Villinger S,
Vonrhein C, Griesinger C, Zweckstetter M, Zeth K (2008). Structure of
the human voltage-dependent anion channel. Proc Natl Acad Sci U S
A 105(40): 15370-15375. doi: 10.1073/pnas.0808115105
19. Hiller S, Garces RG, Malia TJ,Orekhov VY, Colombini M, Wagner G
(2008). Solution structure of the integral human membrane protein
VDAC-1 in detergent micelles. Science 321(5893): 1206-1210. doi:
10.1126/science.1161302
20. Ujwal R, Cascio D, Colletier JP, Faham S, Zhang J, Toro L,Ping P,
Abramson J (2008). The crystal structure of mouse VDAC1 at 2.3 A
resolution reveals mechanistic insights into metabolite gating. Proc
Natl Acad Sci U S A 105(46): 17742-17747. doi:
10.1073/pnas.0809634105
21. Hiller S, Wagner G (2009). The role of solution NMR in the struc-
ture determinations of VDAC-1 and other membrane proteins. Curr
Opin Struct Biol 19(4): 396-401. doi: 10.1016/j.sbi.2009.07.013
22. Geula S, Ben-Hail D, Shoshan-Barmatz V (2012). Structure-based
analysis of VDAC1: N-terminus location, translocation, channel gating
and association with anti-apoptotic proteins. Biochem J 444(3): 475-
485. doi: 10.1042/BJ20112079
23.Abu-Hamad S, Arbel N, Calo D, Arzoine L, Israelson A, Keinan N,
Ben-Romano R, Friedman O, Shoshan-Barmatz V (2009). The VDAC1
N-terminus is essential both for apoptosis and the protective effect of
anti-apoptotic proteins. J Cell Sci 122(Pt 11): 1906-1916. doi:
10.1242/jcs.040188
24. Shi Y, Chen J, Weng C, Chen R, Zheng Y, ChenQ, Tang H (2003).
Identification of the protein-protein contact site and interaction mode
of human VDAC1 with Bcl-2 family proteins. Biochem Biophys Res
Commun 305(4): 989-996. doi: 10.1016/S0006-291X(03)00871-4
25.Arbel N, Ben-Hail D, Shoshan-Barmatz V (2012). Mediation of the
antiapoptotic activity of Bcl-xL protein upon interaction with VDAC1
protein. J Biol Chem 287(27): 23152-23161. doi:
10.1074/jbc.M112.345918
26.Arbel N, Shoshan-Barmatz V (2010). Voltage-dependent anion
channel 1-based peptides interact with Bcl-2 to prevent antiapoptotic
activity. J Biol Chem 285(9): 6053-6062. doi:
10.1074/jbc.M109.082990
27. Arzoine L, Zilberberg N, Ben-Romano R, Shoshan-Barmatz V
(2009). Voltage-dependent anion channel 1-basedpeptides interact
with hexokinase to prevent its anti-apoptotic activity. J Biol Chem
284(6): 3946-3955. doi: 10.1074/jbc.M803614200
28. Keinan N, Tyomkin D, Shoshan-Barmatz V (2010). Oligomerization
of the mitochondrial protein voltage-dependent anion channel is
coupled to the induction of apoptosis. Mol Cell Biol 30(24): 5698-
5709. doi: 10.1128/MCB.00165-10
29. Shoshan-Barmatz V, Israelson A, Brdiczka D, Sheu SS (2006). The
voltage-dependent anion channel (VDAC): function in intracellular
signalling, cell life and cell death. Curr Pharm Des 12(18): 2249-2270.
doi: 10.2174/138161206777585111
30.Shoshan-Barmatz V, Mizrachi D (2012). VDAC1: from structure to
cancer therapy. Front Oncol 2:164. doi: 10.3389/fonc.2012.00164
31.Shoshan-Barmatz V, Mizrachi D, Keinan N (2013). Oligomerization
of the mitochondrial protein VDAC1: from structure to function and
cancer therapy. Prog Mol Biol Transl Sci 117:303-334. doi:
10.1016/B978-0-12-386931-9.00011-8
32. Shoshan-Barmatz V, Golan M (2012). Mitochondrial VDAC1: func-
tion in cell life and death and a target for cancer therapy. Curr Med
Chem 19(5): 714-735. doi: 10.2174/092986712798992110
33. Shoshan-Barmatz V, Keinan N, Zaid H (2008). Uncovering the role
of VDAC in the regulation of cell life and death. J Bioenerg Biomembr
40(3): 183-191. doi: 10.1007/s10863-008-9147-9
34. Zeth K, Meins T, Vonrhein C (2008). Approaching the structure of
human VDAC1, a key molecule in mitochondrial cross-talk. J Bioenerg
Biomembr 40(3): 127-132. doi: 10.1007/s10863-008-9144-z
35. Schlattner U, Tokarska-Schlattner M, Wallimann T (2006). Mito-
chondrial creatine kinase in human health and disease. Biochim Bio-
phys Acta 1762(2): 164-180. doi: 10.10 /j.bbadis.2005.09.004
36. Zalk R, Israelson A, Garty ES, Azoulay-Zohar H, Shoshan-Barmatz V
(2005). Oligomeric states of the voltage-dependent anion channel and
cytochrome c release from mitochondria. Biochem J 386(Pt 1): 73-83.
doi: 10.1042/BJ2004135
37.Geula S, Naveed H, Liang J, Shoshan-Barmatz V (2012). Structure-
based analysis of VDAC1 protein: defining oligomer contact sites. J
Biol Chem 287(3): 2179-2190. doi: 10.1074/jbc.M111.268920
38.Ujwal R, Cascio D, Chaptal V, Ping P, Abramson J (2009). Crystal
packing analysis of murine VDAC1 crystals in a lipidic environment
reveals novel insights on oligomerization and orientation. Channels
(Austin) 3(3): 167-170. doi: 10.4161/chan.3.3.9196
39. Schlattner U, Dolder M, Wallimann T, Tokarska-Schlattner M
(2001). Mitochondrial creatine kinase and mitochondrial outer mem-
brane porin show a direct interaction that is modulated by calcium. J
Biol Chem 276(51): 48027-48030. doi: 10.1074/jbc.M106524200
40. Ben-Hail D, Shoshan-Barmatz V (2014). Purification of VDAC1 from
rat liver mitochondria. Cold Spring Harb Protoc 2014(1): 94-99. doi:
10.1101/pdb.prot073130
41. Gincel D, Silberberg SD, Shoshan-Barmatz V (2000). Modulation of
the Voltage-Dependent Anion Channel (VDAC) by Glutamate1. J Bio-
energ Biomembr 32(6): 571-583. doi: 10.1023/A:1005670527340
42. Colombini M (2012). VDAC structure, selectivity, and dynamics.
Biochim Biophys Acta 1818(6): 1457-1465. doi:
10.1016/j.bbamem.2011.12 .
43. Rostovtseva T, Colombini M (1997). VDAC channels mediate and
gate the flow of ATP: implications for the regulation of mitochondrial
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 27 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
function. Biophys J 72(5): 1954-1962. doi: 10.1016/S0006-
3495(97)78841-6
44. GincelD, Shoshan-Barmatz V (2004). Glutamate interacts with
VDAC and modulates opening of the mitochondrial permeability tran-
sition pore. J Bioenerg Biomembr 36(2): 179-186. doi:
10.1023/B:JOBB.0000023621.72873.9e
45. Rostovtseva TK, Komarov A, BezrukovSM, Colombini M (2002).
VDAC channels differentiate between natural metabolites and syn-
thetic molecules. J Membr Biol 187(2): 147-156. doi: 10.1007/s00232-
001-0159-1
46. Yehezkel G, Hadad N, Zaid H, Sivan S, Shoshan-Barmatz V (2006).
Nucleotide-binding sites in the voltage-dependent anion channel:
characterization and localization. J Biol Chem 281(9): 5938-5946. doi:
10.1074/jbc.M510104200
47. Shoshan-Barmatz V, Gincel D (2003). The voltage-dependent anion
channel: characterization, modulation, and role in mitochondrial func-
tion in cell life and death. Cell Biochem Biophys 39(3): 279-292. doi:
10.1385/CBB:39:3:279
48.Bera AK, Ghosh S, Das S (1995). Mitochondrial VDAC can be phos-
phorylated by cyclic AMP-dependent protein kinase. Biochem Biophys
Res Commun 209(1): 213-217. doi: 10.1006/bbrc.1995.1491
49. Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y,
Bolli R, Cardwell EM, Ping P (2003). Protein kinase Cepsilon interacts
with and inhibits the permeability transition pore in cardiac mito-
chondria. Circ Res 92(8): 873-880. doi:
10.1161/01.RES.0000069215.36389.8D
50. Liberatori S, Canas B, Tani C, Bini L, Buonocore G, Godovac-
Zimmermann J, Mishra OP, Delivoria-Papadopoulos M, Bracci R, Pallini
V (2004). Proteomic approach to the identification of voltage-
dependent anion channel protein isoforms in guinea pig brain synap-
tosomes. Proteomics 4(5): 1335-1340. doi: 10.1002/pmic.200300734
51. Palmieri F, Pierri CL (2010). Mitochondrial metabolite transport.
Essays Biochem 47:37-52. doi: 10.1042/bse0470037
52. Shoshan-Barmatz V, Ben-Hail D (2012). VDAC, a multi-functional
mitochondrial protein as a pharmacological target. Mitochondrion
12(1): 24-34. doi: 10.1016/j.mito.201 .
53.Aram L, Geula S, Arbel N, Shoshan-Barmatz V (2010). VDAC1 cyste-
ine residues: topology and function in channel activity and apoptosis.
Biochem J 427(3): 445-454. doi: 10.1042/BJ20091690
54. Shoshan-Barmatz V, Ben-Hail D, Admoni L, Krelin Y, Tripathi SS
(2015). The mitochondrial voltage-dependent anion channel 1 in tu-
mor cells. Biochim Biophys Acta 1848(10 Pt B): 2547-2575. doi:
10.1016/j.bbamem.2014.10.040
55. Vander Heiden MG, Chandel NS, Li XX, Schumacker PT, Colombini
M, Thompson CB (2000). Outer mitochondrial membrane permeability
can regulate coupled respiration and cell survival. Proc Natl Acad Sci
U S A 97(9): 4666-4671. doi: 10.1073/pnas.090082297
56. Dolder M, Wendt S, Wallimann T (2001). Mitochondrial creatine
kinase in contact sites: interaction with porin and adenine nucleotide
translocase, role in permeability transition and sensitivity to oxidative
damage. Biol Signals Recept 10(1-2): 93-111. doi: 46878
57. Gurnev PA, Rostovtseva TK, Bezrukov SM (2011). Tubulin-blocked
state of VDAC studied by polymer and ATP partitioning. FEBS Lett
585(14): 2363-2366. doi: 10.1016/j.febslet.2011.06.008
58. Abu-Hamad S, Sivan S, Shoshan-Barmatz V (2006). The expression
level of the voltage-dependent anion channel controls life and death
of the cell. Proc Natl Acad Sci U S A 103(15): 5787-5792. doi:
10.1073/pnas.0600103103
59. Arif T, Vasilkovsky L, Refaely Y, Konson A, Shoshan-Barmatz V
(2014). Silencing VDAC1 Expression by siRNA Inhibits Cancer Cell Pro-
liferation and Tumor Growth In Vivo. Mol Ther Nucleic Acids 3:e159.
doi: 10.1038/mtna.2014.9
60.Rone MB, Fan J, Papadopoulos V (2009). Cholesterol transport in
steroid biosynthesis: role of protein-protein interactions and implica-
tions in disease states. Biochim Biophys Acta 1791(7): 646-658. doi:
10.1016/j.bbalip.2009.03.001
61.Aghazadeh Y, Rone MB, Blonder J, Ye X, Veenstra TD, Hales DB,
Culty M, Papadopoulos V (2012). Hormone-induced 14-3-3gamma
adaptor protein regulates steroidogenic acute regulatory protein
activity and steroid biosynthesis in MA-10 Leydig cells. J Biol Chem
287(19): 15380-15394. doi: 10.1074/jbc.M112.339580
62.Yu W, Gong JS, Ko M, Garver WS, Yanagisawa K, Michikawa M
(2005). Altered cholesterol metabolism in Niemann-Pick type C1
mouse brains affects mitochondrial function. J Biol Chem 280(12):
11731-11739. doi: 10.1074/jbc.M412898200
63.Pastorino JG, Hoek JB (2008). Regulation of hexokinase binding to
VDAC. J Bioenerg Biomembr 40(3): 171-182. doi: 10.1007/s10863-
008-9148-8
64.Campbell AM, Chan SH (2008). Mitochondrial membrane choles-
terol, the voltage dependent anion channel (VDAC), and the Warburg
effect. J Bioenerg Biomembr 40(3): 193-197. doi: 10.1007/s10863-
008-9138-x
65.Lee K, Kerner J, Hoppel CL (2011). Mitochondrial carnitine pal-
mitoyltransferase 1a (CPT1a) is part of an outer membrane fatty acid
transfer complex. J Biol Chem 286(29): 25655-62. doi:
10.1074/jbc.M111.228692
66.Martel C, Allouche M, Esposti DD, Fanelli E, Boursier C, Henry C,
Chopineau J, Calamita G, Kroemer G, Lemoine A, Brenner C (2013).
Glycogen synthase kinase 3-mediated voltage-dependent anion chan-
nel phosphorylation controls outer mitochondrial membrane permea-
bility during lipid accumulation. Hepatology 57(1): 93-102. doi:
10.1002/hep.25967
67.Qiu J, Tan Y-W, Hagenston AM, Martel M-A, Kneisel N, Skehel PA,
Wyllie DJA, Bading H, Hardingham GE (3102). Mitochondrial calcium
uniporter Mcu controls excitotoxicity and is transcriptionally re-
pressed by neuroprotective nuclear calcium signals. Nat Commun 4:
2034. doi: 10.1038/ncomms3034
68.Wenger JB, Chun SY, Dang DT, Luesch H, Dang LH (2011). Combi-
nationtherapy targeting cancer metabolism. Med Hypotheses 76(2):
169-172. doi: 10.1016/j.mehy.2010.09.008
69.Cairns RA, Harris IS, Mak TW (2011). Regulation of cancer cell
metabolism. Nat Rev Cancer 11(2): 85-95. doi: 10.1038/nrc2981
70.Maldonado EN, Patnaik J, Mullins MR, Lemasters JJ (2010). Free
tubulin modulates mitochondrial membrane potential in cancer cells.
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 28 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
Cancer Res 70(24): 10192-10201. doi: 10.1158/0008-5472.CAN-10-
2429
71.Mathupala SP, Ko YH, Pedersen PL (2010). The pivotal roles of
mitochondria in cancer: Warburg and beyond and encouraging pro-
spects for effective therapies. Biochim Biophys Acta 1797(6-7): 1225-
1230. doi: 10.1016/j.bbabio.2010.03.025
72.Nakashima RA, Paggi MG, Pedersen PL (1984). Contributions of
glycolysis and oxidative phosphorylation to adenosine 5'-triphosphate
production in AS-30D hepatoma cells. Cancer Res 44(12 Pt 1): 5702-
5706. PMID: 6498833
73.Singleterry J, Sreedhar A, Zhao Y (2014). Components of cancer
metabolism and therapeutic interventions. Mitochondrion 17:50-5.
doi: 10.1016/j.mito.2014.05.010
74.Seyfried TN, Shelton LM (2010). Cancer as a metabolic disease.
Nutr Metab (Lond) 7:7. doi: 10.1186/1743-7075-7-7
75.Seyfried TN (2015). Cancer as a mitochondrial metabolic disease.
Front Cell Dev Biol 3:43. doi: 10.3389/fcell.2015.00043
76. Loeb LA (2001). A mutator phenotype in cancer. Cancer Res 61(8):
3230-3239. PMID: 11309271
77.Gatenby RA, Gillies RJ (2004). Why do cancers have high aerobic
glycolysis? Nat Rev Cancer 4(11): 891-899. doi: 10.1038/nrc1478
78.Hanahan D, Weinberg RA (2011). Hallmarks of cancer: the next
generation. Cell 144(5): 646-674. doi: 10.1016/j.cell.2011.02.013
79.Koppenol WH, Bounds PL, Dang CV (2011). Otto Warburg's contri-
butions to current concepts of cancermetabolism. Nat Rev Cancer
11(5): 325-337. doi: 10.1038/nrc3038
80.Majeed R. HA, Qurishi Y., Qazi A.K., Hussain A., Ahmed M., Najar
R.A., Bhat J.A., Singh S.K. and Saxena A.K. (2012). Therapeutic Target-
ing of Cancer Cell Metabolism: Role of Metabolic Enzymes, Oncogenes
and Tumor Suppressor Genes. J Cancer Sci Ther 4(9): 281-291. doi:
10.4172/1948-5956.1000156
81.Mathupala SP, Ko YH, Pedersen PL (2006). Hexokinase II: cancer's
double-edged sword acting as both facilitator and gatekeeper of ma-
lignancy when bound to mitochondria. Oncogene 25(34): 4777-4786.
doi: 10.1038/sj.onc.1209603
82.Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH (2002).
Mitochondrial bound type II hexokinase: a key player in the growth
and survival of many cancers and an ideal prospect for therapeutic
intervention. Biochim Biophys Acta 1555(1-3): 14-20. doi:
10.1016/s0005-2728(02)00248-7
83. Majewski N, Nogueira V, Robey RB, Hay N (2004). Akt inhibits
apoptosis downstream of BID cleavage via a glucose-dependent
mechanism involving mitochondrial hexokinases. Mol Cell Biol 24(2):
730-740. doi: 10.1128/MCB.24.2.730-740.2004
84.Pastorino JG, Hoek JB, Shulga N (2005). Activation of glycogen
synthase kinase 3beta disrupts the binding of hexokinase II to mito-
chondria by phosphorylating voltage-dependent anion channel and
potentiates chemotherapy-induced cytotoxicity. Cancer Res 65(22):
10545-10554. doi: 10.1158/0008-5472.CAN-05-1925
85.Maldonado EN, Sheldon KL, DeHart DN, Patnaik J, Manevich Y,
Townsend DM, Bezrukov SM, Rostovtseva TK, Lemasters JJ (2013).
Voltage-dependent anion channels modulate mitochondrial metabo-
lism in cancer cells: regulation by free tubulin and erastin. J Biol Chem
288(17): 11920-11929. doi: 10.1074/jbc.M112. .
86. Rostovtseva TK, Sheldon KL, Hassanzadeh E, Monge C, Saks V,
Bezrukov SM, Sackett DL (2008). Tubulin binding blocks mitochondrial
voltage-dependent anion channel and regulates respiration. Proc Natl
Acad Sci U S A 105(48): 18746-18751. doi: 10.1073/pnas.0806303105
87.Timohhina N, Guzun R, Tepp K, Monge C, Varikmaa M, Vija H, Sikk
P, Kaambre T, Sackett D, Saks V (2009). Direct measurement of energy
fluxes from mitochondria into cytoplasm in permeabilized cardiac cells
in situ: some evidence for Mitochondrial Interactosome. J Bioenerg
Biomembr 41(3): 259-275. doi: 10.1007/s10863-009-9224-8
8. Maldonado EN (2017). VDAC-Tubulin, an Anti-Warburg Pro-
Oxidant Switch. Front Oncol 7:4. doi: 10.3389/fonc.2017.00004
89. Colombini M (2004). VDAC: the channel at the interface between
mitochondria and the cytosol. Mol Cell Biochem 256-257(1-2): 107-
115. doi: 10.1023/B:MCBI.0000009862.17396.8d
90.Koren I, Raviv Z, Shoshan-Barmatz V (2010). Downregulation of
voltage-dependent anion channel-1 expression by RNA interference
prevents cancer cell growth in vivo. Cancer Biol Ther 9(12): 1046-
1052. doi: 10.4161/cbt.9.12.11879
91.Arif T, Kerlin Y, Nakdimon I, Benharroch D, Paul A, Dadon-Klein D,
Shoshan-Barmatz V (2017). VDAC1 is a molecular target in glioblasto-
ma, with its depletion leading to reprogrammed metabolism and
reversed oncogenic properties. Neuro Oncol. doi:
10.1093/neuonc/now297
92.Bargaje R, Gupta S, Sarkeshik A, Park R, Xu T, Sarkar M, Halimani
M, Roy SS, Yates J, Pillai B (2012). Identification of novel targets for
miR-29a using miRNA proteomics. PLoS ONE 7(8): e43243. doi:
10.1371/journal.pone.0043243
93.Li QQ, Zhang L, Wan HY, Liu M, Li X, Tang H (2015). CREB1-driven
expression of miR-320a promotes mitophagy by down-regulating
VDAC1 expression during serum starvation in cervical cancer cells.
Oncotarget 6(33): 34924-34940. doi: 10.18632/oncotarget.5318
94.Wang F, Qiang Y, Zhu L, Jiang Y, Wang Y, Shao X, Yin L, Chen J,
Chen Z (2016). MicroRNA-7 downregulates the oncogene VDAC1 to
influence hepatocellular carcinoma proliferation and metastasis. Tu-
mour Biol 37(8): 10235-10246. doi: 10.1007/s13277-016-4836-1
95.Chaudhuri AD, Choi DC, Kabaria S, Tran A, Junn E (2016). Mi-
croRNA-7 Regulates the Function of Mitochondrial Permeability Tran-
sition Pore by Targeting VDAC1 Expression. J Biol Chem 291(12): 6483-
6493. doi: 10.1074/jbc.M115.691352
96. Li X, Wang H, Yao B, Xu W, Chen J, Zhou X (2016). lncRNA
H19/miR-675 axis regulates cardiomyocyte apoptosis by targeting
VDAC1 in diabetic cardiomyopathy. Sci Rep 6:36340. doi:
10.1038/srep36340
97. Manczak M, Reddy PH (2012). Abnormal interaction of VDAC1
with amyloid beta and phosphorylated tau causes mitochondrial dys-
function in Alzheimer's disease. Human moleculargenetics 21(23):
5131-5146. doi: 10.1093/hmg/dds360
98.Cuadrado-Tejedor M, Vilarino M, Cabodevilla F, Del Rio J, Frechilla
D, Perez-Mediavilla A (2011). Enhanced expression of the voltage-
dependent anion channel 1 (VDAC1) in Alzheimer's disease transgenic
mice: an insight into the pathogenic effects of amyloid-beta. Journal
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 29 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
of Alzheimer's disease : JAD 23(2): 195-206. doi: 10.3233/JAD-2010-
100966.
99. Perez-Gracia E, Torrejon-Escribano B, Ferrer I (2008). Dystrophic
neurites of senile plaques in Alzheimer's disease are deficient in cyto-
chrome c oxidase. Acta Neuropathol 116(3): 261-268. doi:
10.1007/s00401-008-0370-6
100. Liao Z, Liu D, Tang L, Yin D, Yin S, Lai S, Yao J, He M (2015). Long-
term oral resveratrol intake provides nutritional preconditioning
against myocardial ischemia/reperfusion injury: involvement of
VDAC1 downregulation. Mol Nutr Food Res 59(3): 454-464. doi:
10.1002/mnfr.201400730
101.Ahmed M, Muhammed SJ, Kessler B, Salehi A (2010). Mitochon-
drial proteome analysis reveals altered expression of voltage depend-
ent anion channels in pancreatic beta-cells exposed to high glucose.
Islets 2(5): 283-292. doi: 10.4161/isl.2.5.12639
102. Gong D, Chen X, Middleditch M, Huang L, Vazhoor Amarsingh G,
Reddy S, Lu J, Zhang S, Ruggiero K, Phillips AR, Cooper GJ (2009).
Quantitative proteomic profiling identifies new renal targets of cop-
per(II)-selective chelation in the reversal of diabetic nephropathy in
rats. Proteomics 9(18): 4309-4320. doi: 10.1002/pmic.200900285
103.Kroemer G, Galluzzi L, Brenner C (2007). Mitochondrial mem-
brane permeabilization in cell death. Physiol Rev 87(1): 99-163. doi:
10.1152/physrev.00013.2006
104.Shoshan-Barmatz V, Arbel N, Arzoine l (2008). VDAC, the voltage-
dependent anion channel: function, regulation & mitochondrial signal-
ing in cell life and death. Cell Science 4:74-118.
105.Lemasters JJ, Holmuhamedov E (2006). Voltage-dependent anion
channel (VDAC) as mitochondrial governator--thinking outside the
box. Biochim Biophys Acta 1762(2): 181-190. doi:
10.1016/j.bbadis.2005.10.006
106.Vander Heiden MG, Li XX, Gottleib E, Hill RB, Thompson CB, Co-
lombini M (2001). Bcl-xL promotes the open configuration of the volt-
age-dependent anion channel and metabolite passage through the
outer mitochondrial membrane. J Biol Chem 276(22): 19414-19419.
doi: 10.1074/jbc.M101590200
107.Biasutto L, Azzolini M, Szabò I, Zoratti M (2016). The mitochon-
drial permeability transition pore in AD 2016: An update. Biochimica
et Biophysica Acta 1863(10): 2515-2530. doi:
10.1016/j.bbamcr.2016.02.012
108. Antignani A, Youle RJ (2006). How do Bax and Bak lead to perme-
abilization of the outer mitochondrial membrane? Curr Opin Cell Biol
18(6): 685-689. doi: 10.1016/j.ceb.2006.10.004
109. Lovell JF, Billen LP, Bindner S, Shamas-Din A, Fradin C, Leber B,
Andrews DW (2008). Membrane binding by tBid initiates an ordered
series of events culminating in membrane permeabilization by Bax.
Cell 135(6): 1074-1084. doi: 10.1016/j.cell.2008.11.010
110.Banerjee J, Ghosh S (2004). Bax increases the pore size of rat
brain mitochondrialvoltage-dependent anion channel in the presence
of tBid. Biochem Biophys Res Commun 323(1): 310-314. doi:
10.1016/j.bbrc.2004.08.094
111.Shimizu S, Tsujimoto Y (2000). Proapoptotic BH3-only Bcl-2 family
members induce cytochrome c release, but not mitochondrial mem-
brane potential loss, and do not directly modulate voltage-dependent
anion channel activity. Proc Natl Acad Sci U S A 97(2): 577-582. doi:
10.1073/pnas.97.2.577
112. Keinan N, Pahima H, Ben-Hail D, Shoshan-Barmatz V (2013). The
role ofcalcium in VDAC1 oligomerization and mitochondria-mediated
apoptosis. Biochim Biophys Acta 1833(7): 1745-1754. doi:
10.1016/j.bbamcr.2013.03.017
113.Weisthal S, Keinan N, Ben-Hail D, Arif T, Shoshan-Barmatz V
(2014). Ca(2+)-mediated regulation of VDAC1 expression levels is
associated with cell death induction. Biochim Biophys Acta 1843(10):
2270-2281. doi: 10.1016/j.bbamcr.2014.03.021
114.Martinou JC, Desagher S, Antonsson B (2000). Cytochrome cre-
lease from mitochondria: all or nothing. Nat Cell Biol 2(3): E41-43. doi:
10.1038/35004069
115.Halestrap AP, McStay GP, Clarke SJ (2002). The permeability
transition pore complex: another view. Biochimie 84(2-3): 153-166.
doi: 10.1016/s0300-9084(02)01375-5
116. Doran E, Halestrap AP (2000). Cytochrome c release from isolated
rat liver mitochondria can occur independently of outer-membrane
rupture: possible role of contact sites. Biochem J 348 (Pt 2):343-350.
doi: 10.1042/0264-6021:3480343
117. Tsujimoto Y, Shimizu S (2002). The voltage-dependent anion
channel: an essential player in apoptosis. Biochimie 84(2-3): 187-193.
doi: 10.1016/s0300-9084(02)01370-6
118. Abu-Hamad S, Zaid H, Israelson A, Nahon E, Shoshan-Barmatz V
(2008). Hexokinase-I protection against apoptotic cell death is medi-
ated via interaction with the voltage-dependent anion channel-1:
mapping the site of binding. J Biol Chem 283(19): 13482-13490. doi:
10.1074/jbc.M708216200
119. Ghosh T, Pandey N, Maitra A, Brahmachari SK, Pillai B (2007). A
role forvoltage-dependent anion channel Vdac1 in polyglutamine-
mediated neuronal cell death. PLoS One 2(11): e1170. doi:
10.1371/journal.pone.0001170
120.Godbole A, Varghese J, Sarin A, Mathew MK (2003). VDAC is a
conserved element of death pathways in plant and animal systems.
Biochim Biophys Acta 1642(1-2): 87-96. doi: 10.1016/s0167-
4889(03)00102-2
121.Lu AJ, Dong CW, Du CS, Zhang QY (2007). Characterization and
expression analysis of Paralichthys olivaceus voltage-dependent anion
channel (VDAC) gene in response to virus infection. Fish Shellfish
Immunol 23(3): 601-613. doi: 10.1016/j.fsi.2007.01.007
122. Zaid H, Abu-Hamad S, Israelson A, Nathan I, Shoshan-Barmatz V
(2005). The voltage-dependent anion channel-1 modulates apoptotic
cell death. Cell Death Differ 12(7): 751-760. doi:
10.1038/sj.cdd.4401599
123. Israelson A, Zaid H, Abu-Hamad S, Nahon E, Shoshan-Barmatz V
(2008). Mapping the ruthenium red-binding site of the voltage-
dependent anion channel-1. Cell Calcium 43(2): 196-204. doi:
10.1016/j.ceca.2007.05.006
124.Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V
(2004). In self-defence: hexokinase promotes voltage-dependent
anion channel closure and prevents mitochondria-mediated apoptotic
cell death. Biochem J 377(Pt 2): 347-355. doi: 10.1042/BJ20031465
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 30 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
125.Tajeddine N, Galluzzi L, Kepp O, Hangen E, Morselli E, Senovilla L,
Araujo N, Pinna G, Larochette N, Zamzami N, Modjtahedi N, Harel-
Bellan A, Kroemer G (2008). Hierarchical involvement of Bak, VDAC1
and Bax in cisplatin-induced cell death. Oncogene 27(30): 4221-4232.
doi: 10.1038/onc.2008.63
126. Tomasello F, Messina A, Lartigue L, Schembri L, Medina C, Reina
S, Thoraval D, CrouzetM, Ichas F, De Pinto V, De Giorgi F (2009). Outer
membrane VDAC1 controls permeability transition of the inner mito-
chondrial membrane in cellulo during stress-induced apoptosis. Cell
Res 19(12): 1363-1376. doi: 10.1038/cr.2009.98
127.Yuan S, Fu Y,Wang X, Shi H, Huang Y, Song X, Li L, Song N, Luo Y
(2008). Voltage-dependent anion channel 1 is involved in endostatin-
induced endothelial cell apoptosis. FASEB J 22(8): 2809-2820. doi:
10.1096/fj.08-107417
128.Shimizu S, Narita M,Tsujimoto Y (1999). Bcl-2 family proteins
regulate the release of apoptogenic cytochrome c by the mitochon-
drial channel VDAC. Nature 399(6735): 483-487. doi: 10.1038/20959
129. Madesh M, Hajnoczky G (2001). VDAC-dependent permeabiliza-
tion of the outer mitochondrial membrane by superoxide induces
rapid and massive cytochrome c release. J Cell Biol 155(6): 1003-1015.
doi: 10.1083/jcb.200105057
130. Betaneli V, Petrov EP, Schwille P (2012). The role of lipids in VDAC
oligomerization. Biophys J 102(3): 523-531. doi:
10.1016/j.bpj.2011.12.049
131.Vaseva AV, Marchenko ND, Ji K, Tsirka SE, Holzmann S, Moll UM
(2012). p53 opens the mitochondrial permeability transition pore to
trigger necrosis. Cell 149(7): 1536-48. doi: 10.1016/j.cell.2012.05.014
132.Ben-Hail D, Shoshan-Barmatz V (2016). VDAC1-interacting anion
transport inhibitors inhibit VDAC1 oligomerization and apoptosis.
Biochim Biophys Acta 1863(7 Pt A): 1612-1623. doi:
10.1016/j.bbamcr.2016.04.002
133. Chen H, Gao W, Yang Y, Guo S, Wang H, Wang W, Zhang S, Zhou
Q, Xu H, Yao J, Tian Z, Li B, Cao W, Zhang Z, Tian Y (2014). Inhibition of
VDAC1 prevents Ca(2)(+)-mediated oxidative stress and apoptosis
induced by 5-aminolevulinic acid mediated sonodynamic therapy in
THP-1 macrophages. Apoptosis 19(12): 1712-1726. doi:
10.1007/s10495-014-1045-5
134.Ben-Hail D, Begas-Shvartz, R., Shalev, M., Gruzman, A. and Sho-
shan-Barmatz. V. (2016). The mitochondrial protein VDAC1 as a target
for novel anti-apoptotic compounds. Cell Death and Dis 16(9):820-
828. doi: 10.1074/jbc.M116.744284
135. Obulesu M, Lakshmi MJ (2014). Apoptosis in Alzheimer's disease:
an understanding of the physiology, pathology and therapeutic ave-
nues. Neurochemical research 39(12): 2301-2312. doi:
10.1007/s11064-014-1454-4
136. Sureda FX, Junyent F, Verdaguer E, Auladell C, Pelegri C, Vilaplana
J, Folch J, Canudas AM, Zarate CB, Palles M, Camins A ( 2011).
Antiapoptotic drugs: a therapautic strategy for the prevention of
neurodegenerative diseases. Curr Pharm Des 17(3): 230-245. doi:
10.2174/138161211795049732
137.Kostin S, Pool L, Elsasser A, Hein S, Drexler HC, Arnon E, Hayaka-
wa Y, Zimmermann R, Bauer E, Klovekorn WP, Schaper J (2003). Myo-
cytes die by multiple mechanisms in failing human hearts. Circ Res
92(7): 715-724. doi: 10.1161/01.RES.0000067471.95890.5C
138. Kroemer G, El-Deiry WS, Golstein P, Peter ME, Vaux D, Vandena-
beele P, Zhivotovsky B, Blagosklonny MV, Malorni W, Knight RA, Pia-
centini M,Nagata S, Melino G (2005). Classification of cell death:
recommendations of the Nomenclature Committee on Cell Death. Cell
Death Differ 12 (Suppl 2):1463-1467. doi: 10.1038/sj.cdd.4401724
139. Marunouchi T, Tanonaka K (2015). Cell Death in the Cardiac Myo-
cyte. Biol Pharm Bull 38(8): 1094-1097. doi: 10.1248/bpb.b15-00288
140. Nawarak J, Huang-Liu R, Kao SH, Liao HH, Sinchaikul S, Chen ST,
Cheng SL (2009). Proteomics analysis of A375 human malignant mela-
noma cells in response to arbutin treatment. Biochim Biophys Acta
1794(2): 159-167. doi: 10.1016/j.bbapap.2008.09.023
141. Jiang N, Kham SK, Koh GS, Suang Lim JY, Ariffin H, Chew FT, Yeoh
AE (2011). Identification of prognostic protein biomarkers in child-
hood acute lymphoblastic leukemia (ALL). J Proteomics 74(6): 843-
857. doi: 10.1016/j.jprot.2011.02.034
142. Liu Z, Bengtsson S, Krogh M, Marquez M, Nilsson S, James P,
Aliaya A, Holmberg AR (2007). Somatostatin effects on the proteome
of the LNCaP cell-line. Int J Oncol 30(5): 1173-1179. doi:
10.3892/ijo.30.5.1173
143.Moin SM, Panteva M, Jameel S (2007). The hepatitis E virus Orf3
protein protects cells from mitochondrial depolarization and death. J
Biol Chem 282(29): 21124-21133. doi: 10.1074/jbc.M701696200
144.Jung JY, Han CR, Jeong YJ, Kim HJ, Lim HS, Lee KH, Park HO, Oh
WM, Kim SH, Kim WJ (2007). Epigallocatechin gallate inhibits nitric
oxide-induced apoptosis in rat PC12 cells. Neurosci Lett 411(3): 222-7.
doi: 10.1016/j.neulet.2006.09.089
145. Voehringer DW, Hirschberg DL, Xiao J, Lu Q, Roederer M, Lock CB,
Herzenberg LA, Steinman L (2000). Gene microarray identification of
redox and mitochondrial elements that control resistance or sensitivi-
ty to apoptosis. Proc Natl Acad Sci U S A 97(6): 2680-2685. doi:
10.1073/pnas.97.6.2680
146.Chen Y, Craigen WJ, Riley DJ (2009). Nek1 regulates cell death
and mitochondrial membrane permeability through phosphorylation
of VDAC1. Cell Cycle 8(2): 257-67. doi: 10.4161/cc.8.2.7551
147.Castagna A, Antonioli P, Astner H, Hamdan M, Righetti SC, Perego
P, Zunino F, Righetti PG (2004). A proteomic approach to cisplatin
resistance in the cervix squamous cell carcinoma cell line A431. Prote-
omics 4(10): 3246-3267. doi: 10.1002/pmic.200400835
148.Leone A, Roca MS, Ciardiello C, Terranova-Barberio M, Vitagliano
C, Ciliberto G, Mancini R, Di Gennaro E, Bruzzese F, Budillon A (2015).
Vorinostat synergizes with EGFR inhibitors in NSCLC cells by increasing
ROS via up-regulation of the major mitochondrial porin VDAC1 and
modulation of the c-Myc-NRF2-KEAP1 pathway. Free Radic Biol Med
89:287-299. doi: 10.1016/j.freeradbiomed.2015.07.155
149.Anis Y (2006). Involvementof Ca2+ in the apoptotic process
friends or foes. Pathways 2: 27.
150.Berridge MJ BM, Roderick HL. (2003). Calcium signalling: Dynam-
ics, homeostasis and remodelling. Nature Review Molecular Cell
Biology 4:517-529. doi: 10.1038/nrm1155
151.Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012). Mito-
chondria as sensors and regulators of calcium signalling. Nat Rev Mol
Cell Biol 13(9): 566-578. doi: 10.1038/nrm3412
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 31 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
152.Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme
CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Kote-
liansky V, Mootha VK (2011). Integrative genomics identifies MCU as
an essential component of the mitochondrial calcium uniporter. Na-
ture: 476(7360): 341-5. doi: 10.1038/nature10234
153.De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R (2011). A
forty-kilodalton protein of the inner membrane is the mitochondrial
calcium uniporter. Nature 476(7360): 336-340. doi:
10.1038/nature10230
154.Palty R, Silverman WF, Hershfinkel M, Caporale T, Sensi SL, Parnis
J, Nolte C, Fishman D, Shoshan-Barmatz V, Herrmann S, Khananshvili
D, Sekler I (2010). NCLX is an essential component of mitochondrial
Na+/Ca2+ exchange. Proc Natl Acad Sci U S A 107(1): 436-441. doi:
10.1073/pnas.0908099107
155.Shoshan-Barmatz V, De S, Meir A (2017). The Mitochondrial
Voltage-Dependent Anion Channel 1, Ca2+ Transport, Apoptosis, and
Their Regulation. Front Oncol 7:60. doi: 10.3389/fonc.2017.00060
156. Bathori G, Csordas G, Garcia-Perez C, Davies E, Hajnoczky G
(2006). Ca2+-dependent control of the permeability properties of the
mitochondrial outer membrane and voltage-dependent anion-
selective channel (VDAC).J Biol Chem 281(25): 17347-17358. doi:
10.1074/jbc.M600906200
157. Gincel D, Zaid H, Shoshan-Barmatz V (2001). Calcium binding and
translocation by the voltage-dependent anion channel: a possible
regulatory mechanism in mitochondrial function. Biochem J 358(Pt 1):
147-155. doi: 10.1042/0264-6021:3580147
158. Rapizzi E, Pinton P, Szabadkai G, Wieckowski MR, Vandecasteele
G, Baird G, Tuft RA, Fogarty KE, Rizzuto R (2002). Recombinant expres-
sion of the voltage-dependent anion channel enhances the transfer of
Ca2+microdomains to mitochondria. J Cell Biol 159(4): 613-624. doi:
10.1083/jcb.200205091
159. Tan W, Colombini M (2007). VDAC closure increases calcium ion
flux. Biochim Biophys Acta 1768(10): 2510-5. doi:
10.1016/j.bbamem.2007.06.002
160. Israelson A, Abu-Hamad S, Zaid H, Nahon E, Shoshan-Barmatz V
(2007). Localization of the voltage-dependent anion channel-1 Ca2+-
binding sites. Cell Calcium 41(3): 235-244. doi:
10.1016/j.ceca.2006.06.005
161. Gincel D, Vardi N, Shoshan-Barmatz V (2002). Retinal voltage-
dependent anion channel: characterization and cellular localization.
Invest Ophthalmol Vis Sci 43(7): 2097-2104. PMID: 12091402
162. Israelson A, Arzoine L, Abu-hamad S, Khodorkovsky V, Shoshan-
Barmatz V (2005). A photoactivable probe for calcium binding pro-
teins. Chem Biol 12(11): 1169-1178. doi:
10.1016/j.chembiol.2005.08.006
163. Csordás G, Renken C, Várnai P, Walter L, Weaver D, Buttle KF,
Balla T, Mannella CA, Hajnóczky G ( 2006). Structural and functional
features and significance of the physical linkage between ER and mi-
tochondria. The Journal of Cell Biology 174(7): 915-921. doi:
10.1083/jcb.200604016
164.de Brito OM, Scorrano L (2008). Mitofusin 2 tethers endoplasmic
reticulum to mitochondria. Nature 456(7222): 605-61. doi:
10.1038/nature07534
65. de Brito OM, Scorrano L (2009). Mitofusin-2 regulates mitochon-
drial and endoplasmic reticulum morphology and tethering: the role
of Ras. Mitochondrion 9(3): 222-226. doi: 10.1016/j.mito.2009.02.005
166.Buttke TM, Sandstrom PA (1994). Oxidative stress as a mediator
of apoptosis. Immunology today 15(1): 7-10. doi: 10.1016/0167-
5699(94)90018-3
167.Fiskum G (2000). Mitochondrial participation in ischemic and
traumatic neural cell death. Journal of neurotrauma 17(10): 843-55.
doi: 10.1089/neu.2000.17.843
168. Patel M, Day BJ, Crapo JD, Fridovich I, McNamara JO (1996).
Requirement for superoxide in excitotoxic cell death. Neuron 16(2):
345-355. doi: 10.1016/S0896-6273(00)80052-5
169.Yuan J, Yankner BA (2000). Apoptosis in the nervous system.
Nature 407(6805): 802-809. doi: 10.1038/35037739
170.Auten RL, Davis JM (2009). Oxygen toxicity and reactive oxygen
species: the devil is in the details. Pediatr Res 66(2): 121-127. doi:
10.1203/PDR.0b0e3181a9eafb
171.Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ
(2003). Production of reactive oxygen species by mitochondria: cen-
tral role of complex III. J Biol Chem 278(38): 36027-36031. doi:
10.1074/jbc.M304854200
172.Quinlan CL, Orr AL, Perevoshchikova IV, Treberg JR, Ackrell BA,
Brand MD (2012). Mitochondrial complex II can generate reactive
oxygen species at high rates in both the forward and reverse reac-
tions. J Biol Chem 287(32): 27255-27264. doi:
10.1074/jbc.M112.374629
173.Tribble DL, Jones DP, Edmondson DE (1988). Effect of hypoxia on
tert-butylhydroperoxide-induced oxidative injury in hepatocytes. Mol
Pharmacol 34(3): 413-420. PMID: 3419429
174.Fridovich I (1997). Superoxide anion radical (O2-.), superoxide
dismutases, and related matters. J Biol Chem 272(30): 18515-18517.
doi: 10.1074/jbc.272.30.18515
175.Veal EA, Day AM, Morgan BA (2007). Hydrogen peroxide sensing
and signaling. Mol Cell 26(1): 1-14. doi: 10.1016/j.molcel.2007.03.016
176.Clerkin JS, Naughton R, Quiney C, Cotter TG (2008). Mechanisms
of ROS modulated cell survival during carcinogenesis. Cancer Lett
266(1): 30-36. doi: 10.1016/j.canlet.2008.02.029
177.Giles GI (2006). The redox regulation of thiol dependent signaling
pathways in cancer. Curr Pharm Des 12(34): 4427-4443. doi:
10.2174/138161206779010549
178.Ushio-Fukai M, Nakamura Y (2008). Reactive oxygen species and
angiogenesis: NADPH oxidase as target for cancer therapy. Cancer Lett
266(1): 37-52. doi: 10.1016/j.canlet.2008.02.044
179.Schenkel LC, Bakovic M (2014). Formation and regulation of
mitochondrial membranes. Int J Cell Biol 2014:709828. doi:
10.1155/2014/709828
180.Zhang Y, Marcillat O, Giulivi C, Ernster L, Davies KJ (1990). The
oxidative inactivation of mitochondrial electron transport chain com-
ponents and ATPase. J Biol Chem 265(27): 16330-16336. PMID:
2168888
181.Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005).
Reactive oxygen species promote TNFalpha-induced death and sus-
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 32 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
tained JNK activation by inhibiting MAP kinase phosphatases. Cell
120(5): 649-661. doi: 10.1016/j.cell.2004.12.041
182. Son Y, Cheong YK, Kim NH, Chung HT, Kang DG, Pae HO (2011).
Mitogen-Activated Protein Kinases and Reactive Oxygen Species: How
Can ROS Activate MAPK Pathways? J Signal Transduct 2011:792639.
doi: 10.1155/2011/792639
183.Beckman KB, Ames BN (1997). Oxidative decay of DNA. J Biol
Chem 272(32): 19633-19636. PMID: 9289489
184. Handy DE, Loscalzo J (2012). Redox regulation of mitochondrial
function. Antioxidants & redox signaling 16(11) :-. doi:
10.1089/ars.2011.4123
185.Mailloux RJ, McBride SL, Harper ME (2013). Unearthing the se-
crets of mitochondrial ROS and glutathione in bioenergetics. Trends
Biochem Sci 38(12): 592-602. doi: 10.1016/j.tibs.2013.09.001
186.Sena LA, Chandel NS (2012). Physiological roles of mitochondrial
reactive oxygen species. Mol Cell 48(2): 158-167. doi:
10.1016/j.molcel.2012.09.025
187.Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P (2008).
Redox regulation of cell survival. Antioxidants & redox signaling
10(8): 1343-1374. doi: 10.1089/ars.2007.1957
188.Barber SC, Mead RJ, Shaw PJ (2006). Oxidative stress in ALS: a
mechanism of neurodegeneration and a therapeutic target. Biochim
Biophys Acta 1762(11-12): 1051-1067. doi:
10.1016/j.bbadis.2006.03.008
189.Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007). Mitochon-
dria, oxidative stress and cell death. Apoptosis 12(5): 913-922. doi:
10.1007/s10495-007-0756-2
190.Ahmad A, Ahmad S, Schneider BK, Allen CB,Chang LY, White CW
(2002). Elevated expression of hexokinase II protects human lung
epithelial-like A549 cells against oxidative injury. Am J Physiol Lung
Cell Mol Physiol 283(3): L573-584. doi: 10.1152/ajplung.00410.2001
191.da-Silva WS, Gomez-PuyouA, de Gomez-Puyou MT, Moreno-
Sanchez R, De Felice FG, de Meis L, Oliveira MF, Galina A (2004). Mito-
chondrial bound hexokinase activity as a preventive antioxidant de-
fense: steady-state ADP formation as a regulatory mechanism of
membrane potential and reactive oxygen species generation in mito-
chondria. J Biol Chem 279(38): 39846-39855. doi:
10.1074/jbc.M403835200
192.Sun L, Shukair S, Naik TJ, Moazed F, Ardehali H (2008). Glucose
phosphorylation and mitochondrial binding are required for the pro-
tective effects of hexokinases I and II. Mol Cell Biol 28(3): 1007-1017.
doi: 10.1128/MCB.00224-07.
193.Bryson JM, Coy PE, Gottlob K, Hay N, Robey RB (2002). Increased
hexokinase activity, of either ectopic or endogenous origin, protects
renal epithelial cells against acute oxidant-induced cell death. J Biol
Chem 277(13): 11392-11400. doi: 10.1074/jbc.M110927200
194.Tikunov A, Johnson CB, Pediaditakis P, Markevich N, Macdonald
JM, Lemasters JJ, Holmuhamedov E (2010). Closure of VDAC causes
oxidative stress and accelerates the Ca(2+)-induced mitochondrial
permeability transition in rat liver mitochondria. Arch Biochem Bio-
phys 495(2): 174-181. doi: 10.1016/j.abb.2010.01.008
195.Han D, Antunes F, Canali R, Rettori D, Cadenas E (2003). Voltage-
dependent anion channels control the release of the superoxide anion
from mitochondria to cytosol. J Biol Chem 278(8): 5557-5563. doi:
10.1074/jbc.M210269200
196.Saeed U, Durgadoss L, Valli RK, Joshi DC, Joshi PG, Ravindranath V
(2008). Knockdown of cytosolic glutaredoxin 1 leads to loss of mito-
chondrial membrane potential: implication in neurodegenerative
diseases. PLoS One 3(6): e2459. doi: 10.1371/journal.pone.0002459
197.Reina S,Checchetto V, Saletti R, Gupta A, Chaturvedi D, Guardi-
ani C, Guarino F, Scorciapino MA, Magri A, Foti S, Ceccarelli M, Messi-
na AA, Mahalakshmi R, Szabo I, De Pinto V (2016). VDAC3 as a sensor
of oxidative state of the intermembrane space of mitochondria:the
putative role of cysteine residue modifications. Oncotarget 7(3): 2249-
2268. doi: 10.18632/oncotarget.6850
198.Ding W, Hudson LG, Liu KJ (2005). Inorganic arsenic compounds
cause oxidative damage to DNA and protein by inducing ROS and RNS
generation in human keratinocytes. Mol Cell Biochem 279(1-2): 105-
112. doi: 10.1007/s11010-005-8227-y
199.Shi H, Hudson LG, Ding W, Wang S, Cooper KL, Liu S, Chen Y, Shi
X, Liu KJ (2004). Arsenite causes DNA damage in keratinocytes via
generation of hydroxyl radicals. Chem Res Toxicol 17(7): 871-878. doi:
10.1021/tx049939e
200. Olson RD, Boerth RC, Gerber JG, Nies AS (1981). Mechanism of
adriamycin cardiotoxicity: evidence for oxidative stress. Life Sci
29(14): 1393-1401. doi: 10.1016/0024-3205(81)90001-1
201.Simamura E, Hirai K, Shimada H, Koyama J, Niwa Y, Shimizu S
(2006). Furanonaphthoquinones cause apoptosis of cancer cells by
inducing the production of reactive oxygen species by the mitochon-
drial voltage-dependent anion channel. Cancer Biol Ther 5(11): 1523-
1529. doi: 10.4161/cbt.5.11.3302
202.Le Bras M, Clement MV, Pervaiz S, Brenner C (2005). Reactive
oxygen species and the mitochondrial signaling pathway of cell death.
Histol Histopathol 20(1): 205-219. doi: 10.14670/HH-20.205
203.Li Q, Sato EF,Zhu X, Inoue M (2009). A simultaneous release of
SOD1 with cytochrome c regulates mitochondria-dependent apopto-
sis. Mol Cell Biochem 322(1-2): 151-159. doi: 10.1007/s11010-008-
9952-9
204.Brahimi-Horn MC, Lacas-Gervais S, Adaixo R, Ilc K, Rouleau M,
Notte A, Dieu M, Michiels C, Voeltzel T, Maguer-Satta V, Pelletier J, Ilie
M, Hofman P, Manoury B, Schmidt A, Hiller S, Pouyssegur J, Mazure
NM (2015). Local mitochondrial-endolysosomal microfusion cleaves
voltage-dependent anion channel 1 to promote survival in hypoxia.
Mol Cell Biol 35(9): 1491-1505. doi: 10.1128/MCB.01402-14
205.Mazure NM (2016). News about VDAC1 in Hypoxia. Frontiers in
Oncology 6: 193. doi: 10.3389/fonc.2016.00193
206.Brahimi-Horn MC, Ben-Hail D, Ilie M, Gounon P, Rouleau M,
Hofman V, Doyen J, Mari B, Shoshan-Barmatz V, Hofman P, Pouysse-
gur J, Mazure NM (2012). Expression of a truncated active form of
VDAC1 in lung cancer associates with hypoxic cell survival and corre-
lates with progression to chemotherapy resistance. Cancer Res 72(8):
2140-2150. doi: 10.1158/0008-5472.CAN-11-3940
207. Ko JH, Gu W, Lim I, Zhou T, Bang H (2014). Expression profiling of
mitochondrial voltage-dependent anion channel-1 associated genes
predicts recurrence-free survival in human carcinomas. PLoS One
9(10): e110094. doi: 10.1371/journal.pone.0110094
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 33 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
208. De Pinto V, Messina A, Lane DJ, Lawen A (2010). Voltage-
dependent anion-selective channel (VDAC) in the plasma membrane.
FEBS Lett 584(9): 1793-1799. doi: 10.1016/j.febslet.2010.02.049
209. Manna B, Bhattacharya T, Kahali B, Ghosh TC (2009). Evolution-
ary constraints on hub and non-hub proteins in human protein inter-
action network: insight from protein connectivity and intrinsic disor-
der. Gene 434(1-2): 50-5. doi: 10.1016/j.gene.2008.12.013
210.Grills C, Jithesh PV, Blayney J, Zhang SD, Fennell DA (2011). Gene
expression meta-analysis identifies VDAC1 as a predictor of poor out-
come in early stage non-small cell lung cancer. PLoS One 6(1): e14635.
doi: 10.1371/journal.pone.0014635
211. Yu H, Kim PM, Sprecher E, Trifonov V, Gerstein M (2007). The
importance of bottlenecks in protein networks: correlation with gene
essentiality and expression dynamics. PLoS Comput Biol 3(4): e59. doi:
10.1371/journal.pcbi.0030059
212.Prezma T, Shteinfer A, Admoni L, Raviv Z, Sela I, Levi I, Shoshan-
Barmatz V (2013). VDAC1-based peptides: novel pro-apoptotic agents
and potential therapeutics for B-cell chronic lymphocytic leukemia.
Celldeath & disease 4:e809. doi: 10.1038/cddis.2013.316
213. Shteinfer-Kuzmine A, Arif T, Krelin Y, Tripathi SS, Paul A, Shoshan-
Barmatz V (2017). Mitochondrial VDAC1-based peptides: Attacking
oncogenic properties in glioblastoma. Oncotarget 8(19): 31329-31346.
doi: 10.18632/oncotarget.15455
214.Patterson RL, van Rossum DB, Kaplin AI, Barrow RK, Snyder SH
(2005). Inositol 1,4,5-trisphosphate receptor/GAPDH complex aug-
ments Ca2+ release via locally derived NADH. Proc Natl Acad Sci U S A
102(5): 1357-1359. doi: 10.1073/pnas.0409657102
215. Vyssokikh M, Zorova L, Zorov D, Heimlich G, Jurgensmeier J,
Schreiner D, Brdiczka D (2004). The intra-mitochondrial cytochrome c
distribution varies correlated to the formation of a complex between
VDAC and the adenine nucleotide translocase: this affects Bax-
dependent cytochrome c release. Biochim Biophys Acta 1644(1): 27-
36. doi: 10.1016/j.bbamcr.2003.10.007
216.Neumann D, Buckers J, Kastrup L, Hell SW, Jakobs S (2010). Two-
color STED microscopy reveals different degrees of colocalization
between hexokinase-I and the three human VDAC isoforms. PMC
Biophys 3(1): 4. doi: 10.1186/1757-5036-3-4
217. Azarashvili T, Krestinina O, Baburina Y, Odinokova I, Grachev D,
Papadopoulos V, Akatov V, Lemasters JJ,Reiser G (2015). Combined
effect of G3139 and TSPO ligands on Ca(2+)-induced permeability
transition in rat brain mitochondria. Arch Biochem Biophys 587: 70-
77. doi: 10.1016/j.abb.2015.10.012
218. Youle RJ, Strasser A (2008). The BCL-2 protein family: opposing
activities that mediate cell death. Nat Rev Mol Cell Biol 9(1): 47-59.
doi: 10.1038/nrm2308
219. Danial NN (2007). BCL-2 family proteins: critical checkpoints of
apoptotic cell death. Clin Cancer Res 13(24): 7254-7263. doi:
10.1158/1078-0432.ccr-07-1598
220. Malia TJ, Wagner G (2007). NMR structural investigation of the
mitochondrial outer membrane protein VDAC and its interaction with
antiapoptotic Bcl-xL. Biochemistry 46(2): 514-525. doi:
10.1021/bi061577h
221. ShimizuS, Konishi A, Kodama T, Tsujimoto Y (2000). BH4 domain
of antiapoptotic Bcl-2 family members closes voltage-dependent
anion channel and inhibits apoptotic mitochondrial changes and cell
death. Proc Natl Acad Sci U S A 97(7): 3100-3105. doi:
10.1073/pnas.97.7.3100
222. Sugiyama T, Shimizu S, Matsuoka Y, Yoneda Y, Tsujimoto Y
(2002). Activation of mitochondrial voltage-dependent anion channel
by apro-apoptotic BH3-only protein Bim. Oncogene 21(32): 4944-
4956. doi: 10.1038/sj.onc.1205621
223. Yamagata H, Shimizu S, Nishida Y, Watanabe Y, Craigen WJ, Tsu-
jimoto Y (2009). Requirement of voltage-dependent anion channel 2
for pro-apoptotic activity of Bax. Oncogene 28(40): 3563-3572. doi:
10.1038/onc.2009.213
224.Huang H, Shah K, Bradbury NA, Li C, White C (2014). Mcl-1 pro-
motes lung cancer cell migration by directly interacting with VDAC to
increase mitochondrial Ca2+ uptake and reactive oxygen species gen-
eration. Cell death & disease 5:e1482. doi: 10.1038/cddis.2014.419
225. Veenman L, Papadopoulos V, Gavish M (2007). Channel-like func-
tions of the 18-kDa translocator protein (TSPO): regulation of apopto-
sis and steroidogenesis as part of the host-defense response. Curr
Pharm Des 13(23): 2385-2405. doi: 10.2174/138161207781368710
226. Veenman L, Shandalov Y, Gavish M (2008). VDAC activation by
the 18 kDa translocator protein (TSPO), implications for apoptosis. J
Bioenerg Biomembr 40(3): 199-205. doi: 10.1007/s10863-008-9142-1
227. Chen Y, Gaczynska M, Osmulski P, Polci R, Riley DJ (2010).Phos-
phorylation by Nek1 regulates opening and closing of voltage depend-
ent anion channel 1. Biochem Biophys Res Commun 394(3): 798-803.
doi: 10.1016/j.bbrc.2010.03.077
228.Zhang X, Bian X, Kong J (2014). The proapoptotic protein BNIP3
interacts with VDAC to induce mitochondrial release of endonuclease
G. PLoS One 9(12): e113642. doi: 10.1371/journal.pone.0113642
229. Kusano H, Shimizu S, Koya RC, Fujita H, Kamada S, Kuzumaki N,
Tsujimoto Y (2000). Human gelsolin prevents apoptosis by inhibiting
apoptotic mitochondrial changes via closing VDAC. Oncogene 19(42):
4807-4814. doi: 10.1038/sj.onc.1203868
230.Qiao H, McMillan JR (2007). Gelsolin segment 5 inhibits HIV-
induced T-cell apoptosis via Vpr-binding to VDAC. FEBS Lett 581(3):
535-540. doi: 10.1016/j.febslet.2006.12.057
231. Carre M, Andre N, Carles G, Borghi H, Brichese L, Briand C, Bra-
guer D (2002). Tubulin is an inherent component of mitochondrial
membranes that interacts with the voltage-dependent anion channel.
J Biol Chem 277(37): 33664-33669. doi: 10.1074/jbc.M203834200
232. Rostovtseva TK, Bezrukov SM (2012). VDAC inhibition by tubulin
and its physiological implications. Biochim Biophys Acta 1818(6):
1526-1535. doi: 10.1016/j.bbamem.2011.11.004
233. Saks V, Guzun R, Timohhina N, Tepp K, Varikmaa M, Monge C,
Beraud N, Kaambre T, Kuznetsov A, Kadaja L, Eimre M, Seppet E
(2010). Structure-function relationships in feedback regulation of
energy fluxes invivo in health and disease: mitochondrial interacto-
some. Biochim Biophys Acta 1797(6-7): 678-697. doi:
10.1016/j.bbabio.2010.01.011
234.Roman I, Figys J, Steurs G, Zizi M (2006). Direct measurement of
VDAC-actin interaction by surface plasmon resonance. Biochim Bio-
phys Acta 1758(4): 479-486. doi: 10.1016/j.bbamem.2006.03.019
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 34 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
235. Xu X, Forbes JG, Colombini M (2001). Actin modulates the gating
of Neurospora crassa VDAC. J Membr Biol 180(1): 73-81. doi:
10.1007/s002320010060
236.Linden M, Karlsson G (1996). Identification of porin as a binding
site for MAP2. Biochem Biophys Res Commun 218(3): 833-836. doi:
10.1006/bbrc.1996.0148
237. Schwarzer C, Barnikol-Watanabe S, Thinnes FP, Hilschmann N
(2002). Voltage-dependent anion-selective channel (VDAC) interacts
with the dynein light chain Tctex1 and the heat-shock protein PBP74.
Int J Biochem Cell Biol 34(9): 1059-1070. doi: 10.1016/s1357-
2725(02)00026-2
238. Bergemalm D, Jonsson PA, Graffmo KS, Andersen PM,
Brannstrom T, Rehnmark A, Marklund SL (2006). Overloading of stable
and exclusion of unstable human superoxide dismutase-1 variants in
mitochondria of murine amyotrophic lateral sclerosis models. The
Journal of neuroscience : the official journal of the Society for Neu-
roscience 26(16): 4147-4154. doi: 10.1523/JNEUROSCI.5461-05.2006
239. Deng HX, Shi Y, Furukawa Y, Zhai H, Fu R, Liu E, Gorrie GH, Khan
MS, Hung WY, Bigio EH, Lukas T, Dal Canto MC, O'Halloran TV, Sid-
dique T (2006). Conversion to the amyotrophic lateral sclerosis pheno-
type is associated with intermolecular linked insoluble aggregates of
SOD1 in mitochondria. Proc Natl Acad Sci U S A 103(18): 7142-7147.
doi: 10.1073/pnas.0602046103
240. Liu J, Lillo C, Jonsson PA, Vande Velde C, Ward CM, Miller TM,
Subramaniam JR, Rothstein JD, Marklund S, Andersen PM, Brannstrom
T, Gredal O, Wong PC, Williams DS, Cleveland DW (2004). Toxicity of
familial ALS-linked SOD1 mutants from selective recruitment to spinal
mitochondria. Neuron 43(1): 5-17. doi: 10.1016/j.neuron.2004.06.016
241. Israelson A, Arbel N, Da Cruz S, Ilieva H, Yamanaka K, Shoshan-
Barmatz V, Cleveland DW (2010). Misfolded mutant SOD1 directly
inhibits VDAC1 conductance in a mouse model of inherited ALS. Neu-
ron 67(4): 575-587. doi: 10.1016/j.neuron.2010.07.019
242. Tan W, Naniche N, Bogush A, Pedrini S, Trotti D, Pasinelli P
(2013). Small peptides against the mutant SOD1/Bcl-2 toxic mito-
chondrial complex restore mitochondrial function and cell viability in
mutant SOD1-mediated ALS. The Journal of neuroscience : the official
journal of the Society for Neuroscience 33(28): 11588-11598. PMID:
23843527
243. Sun J, Liao JK (2002). Functional interaction of endothelial nitric
oxide synthase with a voltage-dependent anion channel. Proc Natl
Acad Sci U S A 99(20): 13108-13113. doi: 10.1073/pnas.202260999
244. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, Shu HB (2005). VISA is an
adapter protein required for virus-triggered IFN-beta signaling. Mol
Cell 19(6): 727-740. doi: 10.1016/j.molcel.2005.08.014
245.Guan K, Zheng Z, Song T, He X, Xu C, Zhang Y, Ma S, Wang Y, Xu
Q, Cao Y, Li J, Yang X, Ge X, Wei C, Zhong H (2013). MAVS regulates
apoptotic cell death by decreasing K48-linked ubiquitination of volt-
age-dependent anion channel 1. Mol Cell Biol 33(16): 3137-3149. doi:
10.1128/MCB.00030-13
246.Viola HM, Adams AM, Davies SM, Fletcher S, Filipovska A, Hool LC
(2014). Impaired functional communication between the L-type calci-
um channel and mitochondria contributes to metabolic inhibition in
the mdx heart. Proc Natl Acad Sci U S A 111(28): E2905-2914. doi:
10.1073/pnas.1402544111
247.Mitra A, Basak T, Datta K, Naskar S, Sengupta S, Sarkar S (2013).
Role of alpha-crystallin B as a regulatory switch in modulating cardio-
myocyte apoptosis by mitochondria or endoplasmic reticulum during
cardiac hypertrophy and myocardial infarction. Cell death & disease
4:e582. doi: 10.1038/cddis.2013.114
248.Lu L, Zhang C, Cai Q, Lu Q, Duan C, Zhu Y, Yang H (2013). Voltage-
dependent anion channel involved in the alpha-synuclein-induced
dopaminergic neuron toxicity in rats. Acta Biochim Biophys Sin
(Shanghai) 45(3): 170-178.doi: 10.1093/abbs/gms114
249. Branco AF, Pereira SL, Moreira AC, Holy J, Sa rdao VA, Oliveira PJ
(2011). Isoproterenol cytotoxicity is dependent on the differentiation
state of the cardiomyoblast H9c2 cell line. Cardiovasc Toxicol 11(3):
191 -. doi: 10.1007/s12012-011-9111-5
250.Fulda S (2009). Tumor resistance to apoptosis. Int J Cancer
124(3): 511-515. doi: 10.1002/ijc.24064
251. Pavlova NN, Thompson CB (2016). The Emerging Hallmarks of
Cancer Metabolism. Cell Metab 23(1): 27-47. doi:
10.1016/j.cmet.2015.12.006
252. Hsu PP, Sabatini DM (2008). Cancer cell metabolism: Warburg
and beyond. Cell 134(5): 703-707. doi: 10.1016/j.cell.2008.08.021
253. Pedersen PL (2008). Voltage dependent anion channels (VDACs):
a brief introduction with a focus on the outer mitochondrial com-
partment's roles together with hexokinase-2 in the "Warburg effect"
in cancer. J Bioenerg Biomembr 40(3): 123-126. doi: 10.1007/s10863-
008-9165-7
254.Shi Y, Jiang C, Chen Q, Tang H (2003). One-step on-column affini-
ty refolding purification and functional analysis of recombinant human
VDAC1. Biochem Biophys Res Commun 303(2): 475-482. doi:
10.1016/s0006-291x(03)00359-0
255. Debatin KM, Poncet D, Kroemer G (2002). Chemotherapy: target-
ing the mitochondrial cell death pathway. Oncogene 21(57): 8786-
8803. doi: 10.1038/sj.onc.1206039
256. Ghobrial IM, Witzig TE, Adjei AA (2005). Targeting apoptosis
pathways in cancer therapy. CA Cancer J Clin 55(3): 178-194. doi:
10.3322/canjclin.55.3.178
257. Hu W, Kavanagh JJ (3112). Anticancer therapy targeting the
apoptotic pathway. Lancet Oncol 4(12): 721-729. doi: 10.1016/S1470-
2045(03)01277-4
258.Kaufmann SH, Vaux DL (2003). Alterations in the apoptotic ma-
chinery and their potential role in anticancer drug resistance. Onco-
gene 22(47): 7414-7430. doi: 10.1038/sj.onc.1206945
259.Kim R, Emi M, Tanabe K, Uchida Y, Arihiro K (2006). The role of
apoptotic or nonapoptotic cell death in determining cellular response
to anticancer treatment. Eur J Surg Oncol 32(3): 269-77. doi:
10.1016/j.ejso.2005.12.006
260. Hail N, Jr. (2005). Mitochondria: A novel target for the chemo-
prevention of cancer. Apoptosis 10(4): 687-705. doi: 10.1007/s10495-
005-0792-8
261.Gallego MA, Joseph B, Hemstrom TH, Tamiji S, Mortier L, Kroe-
mer G, Formstecher P, Zhivotovsky B, Marchetti P (2004). Apoptosis-
inducing factor determines the chemoresistance of non-small-cell lung
carcinomas. Oncogene 23(37): 6282-6291. doi:
10.1038/sj.onc.1207835
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 35 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
262. Debatin KM (1999). Activation of apoptosis pathways by anti-
cancer drugs. Advances in experimental medicine and biology
457:237-244. doi: 10.1007/978-1-4615-4811-9_25
263. Preston TJ, Abadi A, Wilson L, Singh G (2001). Mitochondrial
contributions to cancer cell physiology: potential for drug develop-
ment. Advanced drug delivery reviews 49(1-2): 45-61. doi:
10.1016/S0169-409X(01)00127-2
264.Costantini P, Jacotot E, Decaudin D, Kroemer G (2000). Mito-
chondrion as a novel target of anticancer chemotherapy. J Natl Cancer
Inst 92(13): 1042-1053. doi: 10.1093/jnci/92.13.1042
265.Gogvadze V, Orrenius S, Zhivotovsky B (2009). Mitochondria as
targets for chemotherapy. Apoptosis. doi:
10.1016/j.semcancer.2008.11.007
266. Visvader Jane E, Lindeman Geoffrey J (2012).Cancer Stem Cells:
Current Status and Evolving Complexities. Cell Stem Cell 10(6): 717-
728. doi: 10.1016/j.stem.2012.05.007
267.Chen J, Li Y, Yu T-S, McKay RM, Burns DK, Kernie SG, Parada LF
(2012). A restricted cell population propagates glioblastoma growth
after chemotherapy. Nature 488(7412): 522-526. doi:
10.1038/nature11287
268.Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV,
Chomienne C, Ishikawa F, Schuringa JJ, Stassi G, Huntly B, Herrmann
H, Soulier J, Roesch A, Schuurhuis GJ, Wohrer S, Arock M, Zuber J,
Cerny-Reiterer S, Johnsen HE, Andreeff M, Eaves C (2012). Cancer
stem cell definitions and terminology: the devil is in the details. Nat
Rev Cancer 12(11): 767-75. doi: 10.1038/nrc3368
269.Lee JT, Herlyn M (2007). Old disease, new culprit: Tumor stem
cells in cancer. Journal of Cellular Physiology 213(3): 603-609. doi:
10.1002/jcp.21252
270. Frank NY, Schatton T, Frank MH (2010). The therapeutic promise
of the cancer stem cell concept. The Journal of Clinical Investigation
120(1): 41-50. doi: 10.1172/JCI41004
271. Zhang G, Jiang G, Wang C, Zhong K, Zhang J, Xue Q, Li X, Jin H, Li B
(2016). Decreased expression of microRNA-320a promotes prolifera-
tion and invasion of non-small cell lung cancer cells by increasing
VDAC1 expression. Oncotarget 7(31): 49470-49480. doi:
10.18632/oncotarget.9943
272. Lezi E, Swerdlow RH (2012). Mitochondria in neurodegeneration.
Advances in experimental medicine and biology 942:269-286. doi:
10.1007/978-94-007-2869-1_12
273. Mattson MP, Gleichmann M, Cheng A (2008). Mitochondria in
neuroplasticity and neurological disorders. Neuron 60(5): 748-766.
doi: 10.1016/j.neuron.2008.10.010
274.Manczak M, Park BS, Jung Y, Reddy PH (2004). Differential ex-
pression of oxidative phosphorylation genes in patients with Alzhei-
mer's disease: implications for early mitochondrial dysfunction and
oxidative damage. Neuromolecular Med 5(2): 147-162. doi:
10.1385/NMM:5:2:147
275. Benek O, Aitken L, Hroch L, Kuca K, Gunn-Moore F, Musilek K
(2015). A Direct interaction between mitochondrial proteins and amy-
loid-beta peptide and its significance for the progression and treat-
ment of Alzheimer`s disease. Curr Med Chem. doi:
10.2174/0929867322666150114163051
276. Devi L, Ohno M (2012). Mitochondrial dysfunction and accumula-
tion of the beta-secretase-cleaved C-terminal fragment of APP in
Alzheimer's disease transgenic mice. Neurobiology of disease 45(1):
417-424.doi: 10.1016/j.nbd.2011.09.001
277. Petrozzi L, Ricci G, Giglioli NJ, Siciliano G, Mancuso M (2007).
Mitochondria and neurodegeneration. Biosci Rep 27(1-3): 87-104. doi:
10.1007/s10540-007-9038-z
278. Radi E, Formichi P, Battisti C, Federico A (2014). Apoptosis and
oxidative stress in neurodegenerative diseases. JAD 42 (Suppl 3):
S125-152. PMID: 25056458
279. Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J,
LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van
Der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ,
Roy S, Nicholson DW (1999). Involvement of caspases in proteolytic
cleavage of Alzheimer's amyloid-beta precursor protein and amyloi-
dogenic A beta peptide formation. Cell 97(3): 395-406. doi:
10.1016/s0092-8674(00)80748-5
280.Li M, Ona VO, Guegan C, Chen M, Jackson-Lewis V, Andrews LJ,
Olszewski AJ, Stieg PE, Lee JP, Przedborski S, Friedlander RM (2000).
Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse
model. Science 288(5464): 335-339. doi:
10.1126/science.288.5464.335
281.Friedlander RM (2003). Apoptosis and caspases in neurodegen-
erative diseases. N Engl J Med 348(14): 1365-1375. doi:
10.1056/NEJMra022366
282.Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS,
Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD,
Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001).
Mitochondrial abnormalities in Alzheimer's disease. The Journal of
neuroscience : the official journal of the Society for Neuroscience
21(9): 3017-3023. PMID: 11312286
283. Aleardi AM, Benard G, Augereau O, Malgat M, Talbot JC, Mazat
JP, Letellier T, Dachary-Prigent J, Solaini GC, Rossignol R (2005). Grad-
ual alteration of mitochondrialstructure and function by beta-
amyloids: importance of membrane viscosity changes, energy depriva-
tion, reactive oxygen species production, and cytochrome c release. J
Bioenerg Biomembr 37(4): 207-225. doi: 10.1007/s10863-005-6631-3
284.Ferrer I (2009).Altered mitochondria, energy metabolism, volt-
age-dependent anion channel, and lipid rafts converge to exhaust
neurons in Alzheimer's disease. J Bioenerg Biomembr 41(5): 425-431.
doi: 10.1007/s10863-009-9243-5
285.Ramirez CM, Gonzalez M, Diaz M, Alonso R, Ferrer I, Santpere G,
Puig B, Meyer G, Marin R (2009). VDAC and ERalpha interaction in
caveolae from human cortex is altered in Alzheimer's disease. Mol
Cell Neurosci 42(3): 172-183. doi: 10.1016/j.mcn.2009.07.001
286.Reddy PH (2013). Is the mitochondrial outermembrane protein
VDAC1 therapeutic target for Alzheimer's disease? Biochim Biophys
Acta 1832(1): 67-75. doi: 10.1016/j.bbadis.2012.09.003
287. Yoo BC, Fountoulakis M, Cairns N, Lubec G (2001). Changes of
voltage-dependent anion-selective channel proteins VDAC1 and
VDAC2 brain levels in patients with Alzheimer's disease and Down
syndrome. Electrophoresis 22(1): 172-179. doi: 10.1002/1522-
2683(200101)22:1<172::AID-ELPS172>3.0.CO;2-P
V. Shoshan-Barmatz et al. (2017) VDAC1 as a cancer drug target
OPEN ACCESS | www.cell-stress.com 36 Cell Stress | OCTOBER 2017 | Vol. 1 No. 1
288.Fukada K, Zhang F, Vien A, Cashman NR, Zhu H (2004). Mito-
chondrial proteomic analysis of a cell line model of familial amyo-
trophic lateral sclerosis. Mol Cell Proteomics 3(12): 1211-1223. doi:
10.1074/mcp.M400094-MCP200
289. Marin R, Ramirez CM, Gonzalez M, Gonzalez-Munoz E, Zorzano A,
Camps M, Alonso R, Diaz M (2007). Voltage-dependent anion channel
(VDAC) participates in amyloid beta-induced toxicity and interacts
with plasma membrane estrogen receptor alpha in septal and hippo-
campal neurons. Mol Membr Biol 24(2): 148-160. doi:
10.1080/09687860601055559
290. Reddy PH (2013). Amyloid beta-induced glycogen synthase kinase
3beta phosphorylated VDAC1 in Alzheimer's disease: implications for
synaptic dysfunction and neuronal damage. Biochim Biophys Acta
1832(12): 1913-1921. doi: 10.1016/j.bbadis.2013.06.012
291. Smilansky A, Dangoor L, Nakdimon I, Ben-Hail D, Mizrachi D,
Shoshan-Barmatz V (2015). The Voltage-dependent Anion Channel 1
Mediates Amyloid beta Toxicity and Represents a Potential Target for
Alzheimer Disease Therapy. J Biol Chem 290(52): 30670-30683. doi:
10.1074/jbc.M115.691493
292.Jiang W, Du B, Chi Z, Ma L, Wang S, Zhang X, Wu W, Wang X, Xu
G, Guo C (2007). Preliminary explorations of the role of mitochondrial
proteins in refractory epilepsy: some findings from comparative pro-
teomics. J Neurosci Res 85(14): 3160-3170. doi: 10.1002/jnr.21384
293.Sultana R, Poon HF, Cai J, Pierce WM, Merchant M, Klein JB,
Markesbery WR, Butterfield DA (2006). Identification of nitrated pro-
teins in Alzheimer's disease brain using a redox proteomics approach.
Neurobiology of disease 22(1): 76-87. doi: 10.1016/j.nbd.2005.10.004
294. Roshan R, Shridhar S, Sarangdhar MA, Banik A, Chawla M, Garg
M, Singh VP, Pillai B (2014). Brain-specific knockdown of miR-29 re-
sults in neuronal cell death and ataxia in mice. RNA 20(8): 1287-1297.
doi: 10.1261/rna.044008.113
295.Stary CM, Sun X, Ouyang Y, Li L, Giffard RG (2016). miR-29a dif-
ferentially regulates cell survival in astrocytes from cornu ammonis 1
and dentate gyrus by targeting VDAC1. Mitochondrion 30:248-254.
doi: 10.1016/j.mito.2016.08.013
296.Fatima M, Prajapati B, Saleem K, Kumari R, Mohindar Singh Singal
C, Seth P ( .) Novel insights into role of miR-320a-VDAC1 axis in
astrocyte-mediated neuronal damage in neuroAIDS. Glia 65(2): 250-
263. doi: 10.1002/glia.23089
297.Zimmet P, Alberti KG, Shaw J (2001). Global and societal implica-
tions of the diabetes epidemic. Nature 414(6865): 782-787. doi:
10.1038/414782a
298.Bolen S, Feldman L, Vassy J, Wilson L, Yeh HC, Marinopoulos S,
Wiley C, Selvin E, Wilson R, Bass EB, Brancati FL (2007). Systematic
review: comparative effectiveness and safety of oral medications for
type 2 diabetes mellitus. Ann Intern Med 147(6): 386-399. doi:
10.7326/0003-4819-147-6-200709180-00178
299. Sasaki K, Donthamsetty R, Heldak M, Cho YE, Scott BT, Makino A
(2012). VDAC: old protein with new roles in diabetes. Am J Physiol
Cell Physiol 303(10): C1055-1060. doi: 10.1152/ajpcell.00087.2012
300.Truong AH, Murugesan KD, Youssef A, Makino (2016). Mitochon-
drial Ion Channels in Metabolic Disease,. Springer International Pub-
lishing, Place Published, in: P.I. Levitan, M.D.P.M.A. Dopico (Eds.)
Vascular Ion Channels in Physiology and Disease, pp. 397-419. doi:
10.1007/978-3-319-29635-7_18
301.Lowell BB, Shulman GI (2005). Mitochondrial dysfunction and
type 2 diabetes. Science 307(5708): 384-387. doi:
10.1126/science.1104343
302.Jiang X, Wang X (2000). Cytochrome c promotes caspase-9 acti-
vation by inducing nucleotide binding to Apaf-1. J Biol Chem 275(40):
31199-31203. doi: 10.1074/jbc.C000405200
303.Hay N (2016). Reprogramming glucose metabolism in cancer: can
it be exploited for cancer therapy? Nat Rev Cancer 16(10): 635-49.
doi: 10.1038/nrc.2016.77
304.Johnstone RW, Ruefli AA, Lowe SW (2002). Apoptosis: a link
between cancer genetics and chemotherapy. Cell 108(2): 153-164.
PMID: 11832206
305.Takehara T, Liu X, Fujimoto J, Friedman SL, Takahashi H (2001).
Expression and role of Bcl-xL in human hepatocellular carcinomas.
Hepatology 34(1): 55-61. doi: 10.1053/jhep.2001.25387
306. Ding Z, Yang X, Pater A, Tang SC (2000).Resistance to apoptosis is
correlated with the reduced caspase-3 activation and enhanced ex-
pression of antiapoptotic proteins in human cervical multidrug-
resistant cells. Biochem Biophys Res Commun 270(2): 415-420. doi:
10.1006/bbrc.2000.2432
307. Grobholz R, Zentgraf H, Kohrmann KU, Bleyl U (2002). Bax, Bcl-2,
fas and Fas-L antigen expression in human seminoma: correlation with
the apoptotic index. Apmis 110(10): 724-732. doi: 10.1034/j.1600-
0463.2002.1101006.x
308. Krajewska M, Moss SF,Krajewski S, Song K, Holt PR, Reed JC
(1996). Elevated expression of Bcl-X and reduced Bak in primary colo-
rectal adenocarcinomas. Cancer Res 56(10): 2422-2427. PMID:
8625322
309. Pedersen PL (2007). Warburg, me and Hexokinase 2: Multiple
discoveries of key molecular events underlying one of cancers' most
common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in
the presence of oxygen. J Bioenerg Biomembr 39(3): 211-222. doi:
10.1007/s10863-007-9094-x
310.Mathupala SP, Ko YH, Pedersen PL (2009). Hexokinase-2 bound
to mitochondria: cancer's stygian link to the "Warburg Effect" and a
pivotal target for effective therapy. Semin Cancer Biol 19(1): 17-24.
doi: 10.1016/j.semcancer.2008.11.006
311.Shimizu S, Ide T, Yanagida T, Tsujimoto Y (2000). Electrophysio-
logical study of a novel large pore formed by Bax and the voltage-
dependent anion channel that is permeable to cytochrome c. J Biol
Chem 275(16): 12321-12325. doi: 10.1074/jbc.275.16.12321
312.Pastorino JG, Shulga N, Hoek JB (2002). Mitochondrial binding of
hexokinase II inhibits Bax-induced cytochrome c release and apopto-
sis. J Biol Chem 277(9): 7610-7618. doi: 10.1074/jbc.M109950200
