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Critical Reviews™ in Oncogenesis 23(5-6) 247–267 (2018)
247
Autophagy and Hallmarks of Cancer
Tianzhi Huang,a Xiao Song,a Yongyong Yang,a Xuechao Wan,a Angel A. Alvarez,a Namratha
Sastry,a Haizhong Feng,b Bo Hu,a,* & Shi-Yuan Chenga,*
aKen & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain Tumor Institute, Robert H. Lurie
Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL; bState Key
Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital,
School of Medicine, Shanghai Jiao Tong University, Shanghai, China
*Address correspondence to: Shi-Yuan Cheng, PhD, Ken & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain Tumor Institute,
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Superior, Lurie 6-119, Chicago, IL
60611, E-mail: shiyuan.cheng@northwestern.edu; and to Bo Hu, PhD, Ken & Ruth Davee Department of Neurology, Lou & Jean Malnati Brain
Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Superior, Lurie
6-115, Chicago, IL 60611, E-mail: bo.hu@northwestern.edu.
ABSTRACT: Autophagy is a catabolic program that is responsible for the degradation of dysfunctional or unnecessary
proteins and organelles to maintain cellular homeostasis. Mechanistically, it involves the formation of double-membrane
autophagosomes that sequester cytoplasmic material and deliver it to lysosomes for degradation. Eventually, the material
is recycled back to the cytoplasm. Abnormalities of autophagy often lead to human diseases, such as neurodegeneration
and cancer. In the case of cancer, increasing evidence has revealed the paradoxical roles of autophagy in both tumor inhi-
bition and tumor promotion. Here, we summarize the context-dependent role of autophagy and its complicated molecular
mechanisms in the hallmarks of cancer. Moreover, we discuss how therapeutics targeting autophagy can counter malig-
nant transformation and tumor progression. Overall, the ndings of studies discussed here shed new light on exploiting
the complicated mechanisms of the autophagic machinery and relevant small-molecule modulators as potential antitumor
agents to improve therapeutic outcomes.
KEY WORDS: therapy, autophagosomes, ATGs, cancer, macroautophagy
ABBREVIATIONS: ATG, autophagy-related protein; mTORC1, mammalian target of rapamycin complex 1; ULK1, unc-51-like
autophagy-activating kinase 1; TFEB, transcription factor EB; UBL, ubiquitin-like protein; EMT, epithelial-mesenchymal transi-
tion; CSC, cancer stem cell; CQ, chloroquine
I. INTRODUCTION
Macroautophagy (hereafter referred to as autopha-
gy) is a conserved process by which eukaryotic cells
sequester intracellular material including damaged
organelles, redox-active protein aggregates, and for-
eign matter within double-membraned vesicles (also
known as autophagosomes). These vesicles are then
transported to the lysosome for degradation.1,2 The
autophagic network is a multilayer cellular process
that is tightly controlled by a set of autophagy-rel-
evant factors, including (but not limited to) ATG5,
ATG7, and BECN1.3 Under normal physiological
conditions, baseline levels of autophagy mediate a
key homeostatic function, essentially operating as
an intracellular quality control system. Autophagy
can be upregulated in response to a variety of in-
trinsic or extrinsic stimuli: starvation, growth factor
deprivation, hypoxia, pathogens, and many others.4,5
Autophagy is a critical regulator of cellular homeo-
stasis, and autophagic dysfunction is associated with
human diseases, including Alzheimer’s disease, Par-
kinson’s disease, and cancers.6,7 Of note, autophagy
has complex and context-dependent roles in cancer.
In some contexts, autophagy has a preventive role
during cancer development. Moreover, in most con-
texts autophagy promotes tumorigenesis.7,8 In this
review, we summarize the mechanism of autopha-
gy and its paradoxical roles in cancer. Importantly,
we discuss the molecular and cellular mechanisms
whereby the autophagic network interfaces with
multiple hallmarks of cancer. Finally, we illustrate a
Huang et al.
Critical Reviews™ in Oncogenesis
248
series of molecules and agents targeting autophagy
executors for potential cancer treatments.
II. MECHANISMS OF AUTOPHAGY
The autophagic process involves the sequential
formation of the phagophore (also known as the
isolation membrane), autophagosome, and autol-
ysosome, ultimately leading to the degradation
and recycling of autophagic cargo.9 The molecular
machinery of autophagy is highly conserved from
yeasts to mammals and executed by a group of
autophagy-related proteins (ATGs) that associate
with other proteins to form different complexes in
autophagic ux.9
A. Autophagy Initiation and Phagophore
Nucleation
In yeast, autophagy is initiated at the phagophore
assembly site (PAS).10 Contrarily in mammals,
phagophores are nucleated at an endoplasmic retic-
ulum (ER) -emanating membrane domain enriched
for the lipid phosphatidylinositol 3-phosphate
(PI3P), known as the omegasome.11 Signals that
activate the autophagic process typically originate
from various stressors, including energy or nutrient
shortage, hypoxia, oxidative stress, and other cy-
totoxic insults. The best characterized triggers for
autophagy induction include inactivation of mam-
malian target of rapamycin complex 1 (mTORC1)
under amino acid deprivation12,13 and activation
of AMP-activated protein kinase (AMPK), which
senses changes in the AMP:ATP ratio resulting
from energy starvation.14,15 These two kinases regu-
late autophagy initiation by controlling the activa-
tion of the unc-51-like autophagy-activating kinase
1 (ULK1) complex (known as the Atg1 complex
in yeast), which consists of serine/threonine kinase
ULK1, scaffolding subunit FIP200 (FAK family-
interacting protein of 200 kDa), and regulatory
subunits ATG13 and ATG101.16 In the absence of
starvation (hereafter referred to as fed), mTORC1
binds the ULK1 complex and phosphorylates
both ULK117 and ATG13,18 thereby suppressing
the ULK1 complex function. Upon energy deple-
tion, AMPK directly activates the ULK1 complex
by phosphorylation at multiple sites in the central
intrinsically disordered region (IDR).17,19,20 Addi-
tionally, AMPK indirectly induces autophagy by
inhibiting mTORC1 through phosphorylation of
the regulatory-associated protein of mTOR (RAP-
TOR).21
The activated ULK1 complex then triggers
nucleation of the phagophore by activating down-
stream the Class III phosphoinositide 3-kinase
complex I (PI3KC3-C1). PI3KC3-C1 is another
pivotal autophagy-initiating complex, and consists
of phosphoinositide (PI) kinase vacuolar protein
sorting 34 (VPS34), regulatory subunit BECN1
(Atg6 in yeast), scaffold protein VPS15, and ER-
targeting protein ATG14L.16 ULK1 directly phos-
phorylates VPS34 and BECN1,22 thereby activat-
ing the PI3KC3-C1 complex, and in turn generates
local phosphatidylinositol-3-phosphate (PI3P) in
the phagophore.23 This autophagosome-specic
pool of PI3P is essential for phagophore nucle-
ation.24,25 PI3P promotes recruitment of additional
autophagy-specic PI3P effectors, such as WD-
repeat domain PI-interacting protein 2 (WIPI2).
WIPI2 subsequently recruits the ATG12–ATG16L
conjugation complex for phagophore expansion.26
B. Phagophore Elongation and
Autophagosome Completion
From initiation at the PAS or omegasome, the
phagophore elongates into a cup-shaped structure
and begins to engulf cellular material. In the ex-
pansion stage, two ubiquitin-like protein (UBL)
conjugation systems are required for the elongation
of the phagophore membrane: the ATG12–ATG5
UBL and the microtubule-associated light-chain B
(LC3B, the mammalian orthologue of yeast Atg8)-
phosphatidylethanolamine (PE) UBL.27 ATG12 is a
ubiquitin-like protein, which covalently attaches to
substrates via the carboxyl group of its C-terminal
glycine.28 The ATG12–ATG5 conjugation is medi-
ated by the E1-like enzyme ATG7 and the E2-like
enzyme ATG10.29,30 The ATG12–ATG5 conjugate
then forms a supermolecular complex with AT-
G16L1. This complex is recruited to the phagophore
Authophagy and Hallmarks of Cancer 249
Volume 23, Issues 5-6, 2018
by WIPI2,26 where it acts as an E3-like enzyme for
the LC3-PE UBL.31 Nascent pro-LC3 is cleaved by
the cysteine protease ATG4B, thereby exposing a
glycine residue for its conjugation with PE.32,33 The
processed LC3 is then conjugated to membrane-as-
sociated PE by the E1-like enzyme ATG7 and the
E2-like enzyme ATG3 in concert with the ATG12–
ATG5–ATG16L complex, converting it from a dif-
fuse form (LC3-I) to a membrane-anchored, lipidat-
ed form (LC3-II).34,35 LC3 lipidation is required for
phagophore expansion and closure36,37 and is widely
used as an autophagosome marker. The autophagas-
ome maturation involves the clearance of LC3/Atg8
and PI3P from the autophagasome outer membrane
by ATG4 and YMR1, respectively. Following this
dissociation, the autophagosome can fuse with the
lysosome.38
C. Lysosomal Fusion and Degradation of
Cargo
After formation of the autophagosome is complete,
its outer membrane fuses with the lysosome (vacu-
ole in yeast) to form the structure known as the
autolysosome.39 The autophagosome–lysosome fu-
sion involves the function of three protein families:
Rab GTPases, membrane-tethering factors (such as
HOPS and EPG5), and soluble N-ethylmaleimide-
sensitive factor attachment proteins (SNAREs).
Rab GTPases are located at specic membranes,
which then recruit tethering complexes that act as
bridges to tether the opposing lipid bilayers. These
tethering complexes in turn recruit and promote
SNARE proteins to physically drive fusion of the
autophagosome with the lysosome.40 Additionally,
recent studies have revealed the critical roles of
ATG8 family members in the positioning of au-
tophagosomes near lysosomes. Moreover, these
proteins assist in the assembly of the fusion ma-
chinery, which highlights them as possible hubs for
the coordination of the nal fusion stages of au-
tophagy.41 Degradation of the autophagic cargo is
dependent on a series of lysosomal acid hydrolas-
es. Salvaged nutrients are then released back to the
cytoplasm for protein synthesis and maintenance
of cellular homeostasis.
III. EPIGENETIC, TRANSCRIPTIONAL, AND
POST-TRANSCRIPTIONAL REGULATION
OF AUTOPHAGY
A. Epigenetic Regulation of Autophagy
Accumulating evidence indicates that epigenetic
modications are involved in the control of autoph-
agy.42–53 Post-translational modications of histones
and DNA methylation may affect the chromatin
structure, which leads to the dysregulation of a se-
ries of autophagy-related genes.43–45,48,49 Several his-
tone modications, including H3R17 dimethylation
(me2),54 H3K9me2,45,55,56 H3K27 trimethylation
(me3),48 and H4K16 deacetylation,57 are linked to
autophagy in human cancers.
Nutrient starvation activates the AMPK-fork-
head box protein O3a (FOXO3a) axis to suppress
SKP2. SKP2 repression upregulates protein ar-
ginine methyltransferase CARM1 protein lev-
els.54 The stabilization of CARM1 induces global
H3R17me2 levels in nutrient starvation–induced
autophagy.54 Recent studies have indicated that
H3K9me245,56,58 and H3K27me348 act as repressors
of autophagy. Following autophagy induction,
the G9a methyltransferase and G9a-mediated
H3K9me2 are removed from the target gene pro-
moters, leading to upregulation of autophagy
regulators such as LC3B and sequestosome 1
(SQSTM1/p62).45 EZH2-mediated H3K27me3
epigenetically represses autophagy by downregu-
lating mTOR pathway suppressors such as TSC2,
RGS16, GPI, and RHOA.48 Moreover, EZH2 in-
hibitors such as GSK34359 and UNC199960 signif-
icantly induce autophagy in cancer cells. In addi-
tion to methylation, histone acetylation contributes
to autophagy in tumorigenesis. Downregulation of
H4K16ac is associated with autophagy induction
in human cancer cells, which is mediated by the
histone acetyltransferase hMOF.57 Deacetylation
of H4K16 widely affects autophagy-related gene
expression.57 Other histone modications such as
H2BK120 monoubiquitination,51 H3K56 acetyl-
ation,43,61 and H4K20 methylation43,62 are also in-
volved in autophagy regulation.
Huang et al.
Critical Reviews™ in Oncogenesis
250
B. Transcriptional Regulation of
Autophagy
Emerging studies have demonstrated the key role
played by transcription factors in regulating au-
tophagy in cancer cells.54,63–69 STAT3 is the one of
the most important transcriptional regulators of au-
tophagy-related genes. STAT3 represses BECN1
expression by directly binding to its promoter and
recruiting HDAC3.70 STAT3 also regulates auto-
phagy through PIK3R1 regulation. STAT3 suppress-
es autophagy by transcriptionally upregulating the
PIK3R1 gene products p55α and p50α, which inhib-
it p85α-mediated autophagy.71 Recent studies have
demonstrated that STAT3 also acts as a transcrip-
tional activator of BCL2, BCL2L1, and MCL1,72,73
which are key autophagy-related regulators. Interest-
ingly, both nuclear STAT3 and cytoplasmic STAT3
suppress autophagy in cancer cells. Cytoplasmic
STAT3 directly interacts with EIF2AK2 to inhibit its
enzymatic activity, resulting in decreased autophagy
activator eukaryotic translation initiation factor q al-
pha kinase 2A (EIF2A) phosphorylation.74,75 Further-
more, several STAT3 regulating noncoding RNAs
are involved in autophagy regulation. For example,
the long noncoding RNA HAGLROS, a direct target
of STAT3,76,77 activates the mTOR pathway to pro-
mote autophagy suppression.77
Transcription factor EB (TFEB), a member
of the microphthaimia family, has been reported
to be a key regulator of lysosomal biogenesis and
autophagy.78 Nutrient starvation induces TFEB
nuclear translocation. Nuclear-localized TFEB di-
rectly transcriptionally induces WIPI, VPS11, and
VPS18 in starvation-induced autophagy.78 TFEB
nuclear translocation upregulates autophagy-
related regulators, including ATP6V0D1, LAMP1,
CTSB, MAP1LC3B, and UVRAG.79 Of note, emerg-
ing studies have demonstrated that TFEB serves as
a bridge to mediate upstream regulators and au-
tophagy progression in cancer cells. STUB1 regu-
lates autophagy and mitochondrial biogenesis by
modulating TFEB activity.80 In addition, MAP4K3,
a novel autophagy regulator,81 regulates TFEB
nuclear localization and transcriptional activity by
phosphorylating TFEB at serine 3.81 Several other
genes, such as PEG3,82 AKT,83 and BRD4,84 are
also involved in autophagy regulation by inuenc-
ing TFEB transcription activity.
C. Post-Transcriptional Regulation of
Autophagy
MicroRNAs (miRNAs) are small noncoding RNAs
that are 18–25 nucleotides in length. miRNAs serve
as post-transcriptional regulators of protein-coding
genes by binding to the 3ʹ-untranslated region (UTR)
of target messenger RNAs (mRNAs).85 Emerging
studies report that miRNAs play important roles in
the regulation of autophagy.86–90 miR-30a was the
rst miRNA shown to be involved in autophagy reg-
ulation by targeting BECN1.91 A similar observation
in human chronic myeloid leukemia cells showed
that miR-30a inhibits autophagy by targeting both
BECN1 and ATG5.92 miR-101 is also an autophagy
suppressor.93–95 miR-101-mediated inhibition of au-
tophagy partially depends on three novel targets,
STMN1, RAB5A, and ATG4D.96 Similarly, miR-
376b regulates starvation and mTOR inhibition–re-
lated autophagy through inhibition of ATG4C and
BECN1.97 Finally, miR-23b regulates autophagy to
promote radioresistance in pancreatic cancer cells
by targeting ATG12.98
Unlike miRNAs, long noncoding RNAs (ln-
cRNAs) are RNA transcripts longer than 200
nucleotides with no protein-coding potential.99
Increasingly, reports show the importance of ln-
cRNAs in tumorigenesis by regulating protein
levels through transcriptional, post-transcriptional,
and post-translational levels.99 Since 2013, sev-
eral studies have implicated lncRNAs in autophagy.
APF lncRNA binds and inhibits miR-188-3p. In the
absence of APF lncRNA, miR-188-3p functions
to bind and suppress translation of ATG7 mRNA,
an autophagy-promoting gene. Thus, APF lncRNA
works to inhibit miR-188-3p, thereby disinhibiting
ATG7 gene transcription.100 Knockdown of APF
lncRNA signicantly suppresses ATG7 expression
and autophagy. Additionally, lncRNA HULC, which
is highly upregulated in liver cancer, promotes
autophagy via stabilizing SIRT1 in hepatocellular
carcinoma.101 Finally, MEG3, the most well-known
Authophagy and Hallmarks of Cancer 251
Volume 23, Issues 5-6, 2018
lncRNA involved in autophagy regulation,102–106
interacts with ATG3 mRNA and protects it from
degradation.104 Taken together, these ndings sug-
gest that miRNAs and lncRNAs are important post-
transcriptional regulators of autophagy and act by
regulating autophagy-related genes.
IV. BIPOLAR NATURE OF AUTOPHAGY IN
CANCER
A. Tumor Suppression by Autophagy
Autophagy has been universally demonstrated to
play a tumor-suppressive role at the benign stage,8
and defective autophagy has been connected with
DNA damage and tumorigenesis.7,107
BECN1 is the mammalian orthologue of the
yeast Atg6 gene.108 BECN1 interacts with either
BCL-2 or PI3K Class III (VPS34),109,110 playing
a critical role in the regulation of both autophagy
and cell death.109,111 Adult mice having monoallelic
deletion of Becn1 (BECN1+/−) showed increased
DNA damage and a higher incidence of spontane-
ous lung cancer, liver cancer, and lymphomas.112,113
Allelic deletion of Becn1 has been reported in other
tumor types, such as prostate, breast, and ovar-
ian cancers.108,114 BECN1 is positively regulated
by the ultraviolet radiation resistance–associated
gene (UVRAG) and Bax-interacting factor 1 (BIF-
1). Both of these proteins enhance the interaction
between BECN1 and VPS34, leading to increased
autophagy.115,116 Mutations in UVRAG and low ex-
pression of BIF-1 have been observed in several
types of cancers.116–118 Moreover, mice with system
mosaic deletion of Atg5 or liver-specic Atg7 de-
ciency also develop liver tumors.119 Together, these
ndings suggest that autophagy plays a key role in
repressing tumorigenesis.
Mitophagy is the selective degradation of dam-
aged mitochondria by autophagy. Dysfunctional
mitochondria promote activation of PTEN-induced
putative kinase 1 (PINK1), which further activates
the E3 ligase parkin (encoded by PARK2) to ubiq-
uitinate mitochondrial substrates, resulting in the
selective degradation of damaged mitochondria by
the autophagy machinery.120,121 Mitophagy helps to
maintain mitochondrial quality and reduce oxidative
stress. Park2 has been shown to function as a tumor
suppressor gene.122 Like Becn1 deletion, Park2 de-
letion in mice leads to increased hepatocellular car-
cinoma,123 implying that defective mitophagy and
oxidative stress contribute to tumor tumorigenesis.
p62, a prominent autophagy substrate, is an
adaptor protein that possesses various binding
motifs. It functions by recruiting proteins and as-
sembling them into complexes.124 Nuclear factor
(erythroid-derived 2) -related factor 2 (NRF2) is
activated by p62125 and is responsible for activating
the transcription of antioxidant defense genes.126 In
the absence of cellular stress, kelch-like ECH–as-
sociated protein 1 (KEAP1), a component of the
CUL3–RBX1 E3 ligase complex, binds and in-
hibits NRF2 activity. However, in the presence of
oxidative stress, p62 expression increases. Thus,
p62 competitively binds KEAP1, thereby releas-
ing NRF2. NRF2 then translocates to the nucleus
and activates the expression of antioxidant defense
genes, promoting cell survival and tumorigenesis.125
Autophagy deciency via liver-specic deletion of
Atg7 in mice results in p62 accumulation and NRF2
activation, increasing the expression of NRF2-target
genes. Liver tumors originate from autophagy-de-
cient hepatocytes, which can be partially suppressed
by p62 deletion.119 Deciency in p62 or NRF2 sup-
presses the development of Ras-driven non-small-
cell lung cancer in mouse models.127,128 Furthermore,
activating mutations of NRF2 and inactivation mu-
tations of its negative regulator, KEAP1, are found
in various types of cancers, implying that p62 and
NRF2 function as oncogenes while KEAP1 func-
tions as a tumor suppressor.129–131
B. Tumor Promotion by Autophagy
Although autophagy inhibits early tumor initiation
and growth, the principal effect of autophagy is to
promote tumor growth. In many cases, cancer cells
show increased autophagy dependency than normal
cells. This context-dependent nature of autophagy
likely results from the elevated metabolic and bio-
synthetic demands of dysregulated proliferating
cancer cells.
Huang et al.
Critical Reviews™ in Oncogenesis
252
Basal levels of autophagy are essential for nor-
mal tissue homeostasis.132 Autophagy was initially
shown to support the survival of yeast under star-
vation conditions through maintaining amino acid
levels and activating the expression of genes in re-
sponse to starvation.133,134 Deletion of Atg5 or Atg7
in mouse brains causes polyubiquitinated protein
accumulation and leads to neurodegeneration.135,136
This suggests that clearance of abnormal proteins
by autophagy is crucial for the survival of neurons.
Becn1−/− mice are embryonic lethal.112 Neonatal
Atg5-decient mice survive for a much shorter time
than wild-type mice. Moreover, Atg5-decient neo-
nates display signs of reduced amino acid concen-
tration and ATP levels,137 suggesting that they suffer
from a metabolic crisis. These ndings support an
important and conserved role for autophagy in nor-
mal cell survival in response to metabolic stress.
The major function of autophagy is to collect,
degrade, and recycle intracellular material when
cells are in starvation. Autophagy can supply mi-
tochondrial substrates in the form of amino and
fatty acids, further promoting tumor cell growth.
Impaired autophagy in cancer cells leads to the ac-
cumulation of morphologically and functionally ab-
normal mitochondria.119 Experimentally induced au-
tophagy deciency in tumor cells results in decient
ATP and lack of key tricarboxylic acid (TCA) -cycle
intermediates, and leads to mitochondrial dysfunc-
tion. Mitochondrial dysfunction is mainly exempli-
ed by generation of toxic reactive oxygen species
(ROS) and mitochondrial damage, promoting accu-
mulation of damaged mitochondria resulting from
a failure of clearance by mitophagy.138,139 However,
the precise mechanisms of autophagy’s support of
mitochondrial function are still under investigation.
Autophagy is vigorously stimulated by vari-
ous stressors in cancer cells to support their high
metabolic demands. In conditions in which apop-
tosis is inhibited, autophagic cancer cells enter a
state of quiescence, which allows them to survive
for weeks. When metabolites and nutrients become
readily available again, these cells are restored to
their normal growth conditions.140 Glucose depriva-
tion and hypoxia, typical physiological stresses in
the tumor microenvironment, activate autophagy in
cancer cells to support survival.141,142 Pharmacologi-
cal inhibition of autophagy or deletion of essential
autophagy genes suppresses cancer cell growth in
normal and stress conditions.142,143
A large number of cancer cell lines have a high
basal level of autophagic activities even without
stressors. Several oncogenes (e.g., RAS and BRAF)
that promote cancer cell growth also increase the
basal level of autophagy.144,145 It is hypothesized that
both RAS and BRAF function using similar mecha-
nisms. Activating mutations in RAS and BRAF, al-
though frequent in cancer, are mutually exclusive, as
concurrent mutations arising in both genes are ex-
tremely rare.146 Ras-activated cancer cells are highly
dependent on autophagy to support their survival
under basal and especially stressful conditions.145 K-
RAS translocates into the mitochondria and causes a
disruption of Complex I. K-RAS activation signi-
cantly suppresses cancer cell mitochondrial respira-
tion and impairs acetyl-CoA production. This results
in increased dependency on autophagy to provide the
necessary substrates for acetyl-CoA biosynthesis to
promote TCA cycle activation.145,147 Genetic or phar-
macologic inhibition of autophagy in cancer cells
with K-RAS activation causes increased ROS and
DNA damage and decreased mitochondrial oxida-
tive phosphorylation,139,145 resulting in robust tumor
suppression.139 Human non-small-cell lung cancer
cells with BRAF activation mutations display high
levels of autophagic activity. Inhibition of autophagy
through Atg7 deciency (Atg7−/−) suppresses the pro-
gression of BrafV600E-driven tumors and accumulates
defective mitochondria.144 Overall, this implies that
the dysregulated mitochondrial metabolism caused
by impaired autophagy promotes tumor growth.
V. AUTOPHAGY AND THE HALLMARKS OF
CANCER
A. Autophagy Sustains Proliferation
One of the key characteristics of cancer cells is sus-
tained proliferation.148 Normal cells have precise con-
trols of cell cycle progression to maintain proper cell
growth and function. However, tumor cells obtain
unlimited proliferating potential by bypassing cell
Authophagy and Hallmarks of Cancer 253
Volume 23, Issues 5-6, 2018
cycle check points, due to mutations in genes such as
TP53 and Retinoblastoma (Rb).148 Basal levels of au-
tophagy in normal tissue maintain genome integrity
and prevent tumorigenesis.7,107 Autophagy deciency
by Atg5 or Becn1 deletion (Atg5−/− or Becn1−/−) causes
early death in mice.112,137 Moreover, mice with mo-
saic deletion of Atg5 or monoallelic deletion of Becn1
show a high incidence of liver cancer.112,119 In cancer
cells, the PI3K/AKT pathway is often activated to
promote cell proliferation through PI3K-activating
mutations, increased expression of AKT, EGFR over-
expression, HER-2 amplication, or PTEN loss, fol-
lowed by mTOR activation. Interestingly, mTORC1
is a major negative regulator of autophagy.149–151
BCL2 that is often overexpressed in cancer cells
also inhibits autophagy through inhibitory binding to
BECN1.110,111 TP53 is the most commonly mutated
gene in human cancers and encodes the p53 protein.
Activation of p53 via starvation or DNA damage ac-
tivates autophagy, which may occur via inhibition of
mTOR.152,153 These ndings suggest that autophagy
suppresses cancer cell growth, which is consistent
with its role as tumor suppressor.
However, as discussed previously, the role of
autophagy in cancer is contextual. High levels of
autophagy are also observed in RAS-BRAF-driven
cancer cells, and autophagy is essential for these tu-
mor cells to grow under both normal and starvation
conditions.144,145 Impaired autophagy in these tumors
greatly inhibits tumor cell growth and tumor pro-
gression, revealing the role of autophagy in sustain-
ing tumor cell proliferation. Taken together, these
cases show that the complexity of tumors and the
role of autophagy in regulating tumor cell prolifera-
tion are highly context-dependent.
B. Autophagy Promotes Epithelial–
Mesenchymal Transition
Epithelial–mesenchymal transition (EMT), another
hallmark of cancer, is the process by which epithe-
lial cells lose their adhesive properties and become
more migratory and invasive mesenchymal cells.
Autophagy and EMT both play crucial roles in hu-
man cancer progression.154,155 However, the inter-
play between autophagy and EMT remains unclear.
Here, we focus on elucidating the intricate relation-
ship between them.
Autophagy is an important mechanism by which
cancer cells evade apoptosis and is a prerequisite
of tumor metastasis.156,159 Previous studies have
revealed that autophagy is positively correlated to
cancer cell EMT. Autophagy can activate hepato-
cellular carcinoma (HCC) cell EMT, which can
subsequently promotes cell invasion.160 Autophagy
impairment through chloroquine (CQ) treatment
or Atg3 and Atg7 silencing inhibits EMT in HCC
cells.160 Moreover, knockdown of BECN-1, a key
autophagy activator, remarkably suppresses EMT
in colon cancer cells.161 Interestingly, ULK2, which
phosphorylates the BECN-1 initiation complex,
may also promote EMT in lung cancer cells.162 Sim-
ilarly, cisplatin treatment activates autophagy in na-
sopharyngeal carcinoma, and autophagy inhibition
impairs EMT in this progression.163
Contrary to these ndings, a number of studies
have shown negative crosstalk between autophagy
and EMT in cancer cells, which is likely due to the
bipolar nature of autophagy. Several reports have
shown that anticancer agents, such as the Aurora ki-
nase inhibitors alisertib164,165 and danusertib,166,167 ac-
tivate autophagy but supress EMT in cancer cells. In
ovarian cancer, autophagy inhibition through Atg7
knockdown promotes EMT via activation of the
ROS/Heme Oxygenase-1 (ROS/HO-1) pathway.168
Similarly, knockdown of ATG5, ATG7, or BECN-
1 in glioblastoma induces autophagy impairment,
which leads to promotion of cancer cell by induc-
ing EMT.169 The direct interaction between CDH6
and GABARAP as well as BNIP3 and BNIP3L in
thyroid cancer suppresses autophagy to promote
EMT.170 TWIST, the basic helix-loop-helix tran-
scription factor, is the hallmark of EMT and plays
crucial roles in cancer metastasis.171,172 Recent stud-
ies have indicated that the degradation of TWIST
underlies autophagy-inhibiting EMT in cancer cells.
The death effector domain–containing DNA-bind-
ing protein (DEDD) directly interacts with PI3KC3/
BECN-1 to induce autophagy-mediated lysosomal
degradation of SNAIL and TWIST,173 which conse-
quentially inhibit EMT. Finally, autophagy impair-
ment stabilizes TWIST1 to promote EMT.174
Huang et al.
Critical Reviews™ in Oncogenesis
254
Recent studies indicate that p62 and TGF-β me-
diate crosstalk between autophagy and EMT. Ear-
lier studies revealed that p62, an autophagy adap-
tor protein, may bind to EMT regulators to affect
EMT progression. For example, p62 sustains a level
of HDAC6 to promote EMT in prostate cancer.175
p62 also interacts with TWIST to promote EMT
by inhibiting its degradation.174 Similarly, p62 in-
creases EMT in cancer cells by stabilizing SMAD4
and TWIST,176and it has been shown to increase the
transcriptional activity of NF-κB to promote EMT
by enhancing the nuclear translocation of p65.177
TGF-β signaling is the most important regulator
of EMT in human cancers.178,179 It has been shown
that TGF-β plays a crucial role in crosstalk between
EMT and autophagy by promoting autophagy in
cancers. TGF-β treatment induces autophagy in
hepatocellular carcinoma (HCC)160,180 by induc-
ing autophagy regulators such as BECN-1, ATG5,
and ATG7.180 Interestingly, autophagy impairment
by CQ or ATG5 knockdown suppresses TGF-β2–
induced EMT.181 Additionally, TGF-β2 activates
autophagy via the SMAD and JNK pathways in
glioma cell lines.182 Autophagy inhibition blocks
TGF-β2–induced EMT by inuencing mitochon-
drial trafcking and membrane potential.
C. Role of Autophagy in Tissue Invasion
and Metastasis
Tumor cells have the capability for local invasion
and distant metastasis. The cascade of tumor in-
vasion and metastasis can be divided into a series
of steps: local invasion, intravasation into nearby
blood and lymphatic vessels, transit of cancer cells
through the circulatory system, extravasation, for-
mation of small nodules of cancer cells, and nally
outgrowth of micrometastatic lesions into macro-
scopic tumors. This process requires the transloca-
tion of cancer cells to new microenvironments, in
which metastatic tumor cells must overcome numer-
ous challenges to survive. These include altered nu-
trient supply, immune surveillance, and T-cell–me-
diated killing mechanisms.183,184 Given the key role
of autophagy as an adaptive response to stress, its
involvement in the different stages of the metastatic
cascade has been postulated.159 Indeed, autophagic
ux has been found to be upregulated by the differ-
ent environmental stressors that promote invasion
and metastasis of cancer cells, such as hypoxia and
nutrient deprivation.185 In addition, recent studies
have identied an association between increased
punctate staining for LC3B and metastasis of vari-
ous cancers, including human breast cancer, mela-
noma, and HCC.186–188
Autophagy can either promote or impede cell
invasion and metastasis. At the initial steps of me-
tastasis, autophagy promotes the survival of tumor
cells from hypoxia and metabolic stress by reducing
tumor cell necrosis. Consequently, autophagy re-
duces the inltration of macrophages at the primary
tumor site, which is required for the initiation of
metastasis.189,190 During detachment from the extra-
cellular matrix, autophagy is induced in tumor cells
to overcome anoikis, a type of cell death signal trig-
gered by the absence of anchorage to the extracel-
lular matrix.191,192 A connection between autophagy,
EMT, and invasion has also been seen in HCC and
lung cancer cells, where autophagy is critical for
EMT and invasion of tumor cells.160,162
Upon successful extravasation, autophagy is
proposed to facilitate tumor cell dormancy by pro-
moting quiescence, a process that is also necessary
for the maintenance of cancer stem cells.193 Indeed,
autophagy has been shown to be induced by the tu-
mor suppressor gene aplasia Ras homolog member I
(ARHI) to increase tumor cell dormancy.194 The dor-
mancy of tumor cells has also been suggested to re-
sult in resistance to genotoxic therapies that primar-
ily target proliferating cells.195 If autophagy is truly
required for dormancy, the combination of genotoxic
therapy with autophagy inhibition comes into focus
as a therapeutic option to eliminate dormant tumor
cells and thereby limit metastatic disease.
The studies previously described suggest that
autophagy prevents initiation of invasion and me-
tastasis by preventing tumor necrosis and inamma-
tion. However, once the tumor cells have entered a
new microenvironment, autophagy helps them sur-
vive and maintain dormancy until they successfully
establish distant colonies. Therefore, autophagy
may be regulated differently at the various stages of
Authophagy and Hallmarks of Cancer 255
Volume 23, Issues 5-6, 2018
metastasis in a way that has signicance for the use
of autophagy modulators in cancer therapy.
D. Autophagy Reprograms Tumor
Metabolism
It has been established that tumor cells have to
change their metabolic pathways to meet the height-
ened metabolic requirements necessary for tumor
survival and unconstrained proliferation.196 To ac-
complish these goals, tumor cells have been shown to
use various sources of energy. Indeed, some tumors
employ increased aerobic glycolysis rather than oxi-
dative phosphorylation to generate the biosynthetic
intermediates required for proliferation (termed the
Warburg effect).197 This is an acquired property of
tumors caused by the impaired mitochondrial me-
tabolism that also helps tumor cell survival in hy-
poxic microenvironments caused by dysfunctional
vasculature. In the absence of pyruvate, other sub-
strates are required to undergo the tricarboxylic
acid (TCA) cycle for ATP synthesis, and autophagy
can provide these substrates by recycling intracel-
lular macromolecules.198 Autophagy can lead to the
degradation of various substrates, thereby providing
metabolites for numerous metabolic pathways.199
For instance, autophagy can provide sugars and nu-
cleosides for glycolysis by degrading carbohydrates
and DNA, respectively. It can also provide metabo-
lites for the TCA cycle by degrading proteins and
lipids. Therefore, autophagy plays an important role
in reprogramming metabolic pathways to promote
tumor cell survival.
In addition to cancer metabolism, autophagy
also functions in the metabolic crosstalk between
tumor cells and other stromal components, such as
pancreatic stellate cells.200 Autophagy is required for
stellate cells to secrete metabolic substrates, such as
the nonessential amino acid alanine, to support pan-
creatic cancer mitochondrial metabolism.201
E. Implications of Autophagy in Cancer
Stem Cells
Cancer stem cells (CSCs) are dened as a small
subset of cancer cells within a tumor that can self-
renew and generate heterogeneous lineages of can-
cer cells that make up the tumor.202,203 CSCs are in-
trinsically resistant to conventional chemotherapy
and radiation treatment, and are postulated to con-
tribute to treatment failure and tumor recurrence.204
Therefore, targeting CSCs represents a useful strat-
egy to improve the effectiveness of therapeutic in-
terventions.
The involvement of autophagy in the physiol-
ogy of CSCs is complicated and is not yet fully
elucidated. Accumulating evidence suggests that
autophagy plays critical roles in the maintenance
and function of various normal stem cells. Given
the similarities between normal stem cells and
CSCs, it is expected that autophagy may be cru-
cial in the maintenance and function of CSCs. The
expression of the CSC marker CD133 is positively
correlated with the expression of autophagy-related
proteins ATG5, ATG12, and LC3. Autophagy in-
duction markedly enhances the radiation resistance
of CD133+ glioma stem cells (GSCs).205 In CD44+/
CD24−/low breast CSCs (BCSCs), ATG4 regulates
BCSC populations by promoting their self-renewal
in vitro and tumor growth in vivo.206,207 Along
similar lines, CQ-mediated autophagy inhibition
depleted the CD44+/CD24–/low BCSC population in
triple-negative breast cancer in both preclinical and
clinical settings.208 Moreover, inhibition of autopha-
gy by ATG4B knockdown altered GSC phenotypes.
Inhibition of ATG4B using a specic antagonist,
NSC185058, sensitized GSCs to gamma-irradiation
and reduced their capability to form glioma tumor
spheres. These ndings illustrate that autophagy is a
crucial regulator of GSCs.143 A better understanding
of the molecular mechanisms governing autophagic
responses in various CSCs may prove critical for
the development of novel antineoplastic therapy
aiming at tumor eradication.
F. Autophagy and Cancer Cell
Resistance to Therapy
Most anticancer therapies, including radiation ther-
apy, chemotherapy, and targeted therapies, invoke
autophagy in tumor cells209–211 which predominantly
functions as a cytoprotective mechanism against
Huang et al.
Critical Reviews™ in Oncogenesis
256
therapy-induced stress responses.212,213 Preclinical
data from immunodecient host animal models in-
dicate that pharmacological suppression of autopha-
gy with inhibitors such as 3-methyladenine, CQ, or
hydroxychloroquine (HCQ) can augment cytotox-
icity in combination with various anticancer treat-
ments. These treatments include conventional che-
motherapeutics (e.g., cisplatin,214 5-uorouracil,215
temozolomide,216 and epirubicin217), radiation ther-
apy,218,219 targeted agents (e.g., getinib22), and anti-
angiogenic agents (e.g., bevacizumab221). Moreover,
genetic silencing of autophagy regulatory genes,
such as ATG5, ATG7, BECN-1, and LC3, leads to an
enhanced sensitivity of tumor cells to chemothera-
py, 214 ionizing radiation,222 and antiangiogenic ther-
apy.142,223 The mechanism of autophagy-mediated
cancer therapy resistance includes removal of geno-
toxic ROS,224,225 blockade of apoptosis,226,227 and
maintenance of the CSC pool.204,228 Such preclinical
evidence supports the idea of targeting autophagy as
a promising therapeutic strategy to overcome cancer
drug resistance. Multiple ongoing clinical trials are
deciphering the combination effect of CQ or HCQ
with various therapies.213,229
Autophagy is also involved in the induction
of robust antitumor immune responses, which
play a pivotal role in eliminating tumor cells after
cytotoxic chemotherapies.230 Like tumor cells, the
immune system derives benets from the cytopro-
tective effects of autophagy, and therapy-induced
autophagy in tumor cells can cause immunogenic
cell death, leading to efcient recognition by the
immune system.231,232 Thus, autophagy-targeted
therapy may generate undesirable effects that
weaken the host immune system against malignant
cells upon treatment. This assertion is evidenced
by studies of immunocompetent hosts showing
that defective autophagy can limit (rather than
increase) the sensitivity of tumors to therapies
that activate anticancer immune responses.222,223
Currently, available clinical data on CQ or HCQ
combinational therapy is disappointing, indicating
that the immune-promoting function of autophagy
seems to dominate over its tumor cytoprotective
effect in response of anticancer therapy.223 Future
efforts should be dedicated to conrming the func-
tion of autophagy activation in malignant cells
upon multiple anticancer regimens in the presence
of a functional immune system.
VI. TARGETING AUTOPHAGY FOR CANCER
THERAPEUTICS
Cytoprotective autophagy is an important response
to treatment with chemotherapeutic agents and ra-
diation.234 In most cases, autophagy supports the
survival of cancer cells in anticancer therapy; how-
ever, under certain conditions it fosters cell death.235
In any case, strategies aimed at the modulation of
autophagy bear the potential to improve the efcacy
of chemotherapy and radiation therapy. The optimal
strategy seems to depend on tumor type, stage, ge-
netic context, and specic treatment.236 Additional-
ly, autophagy manipulation might sensitize resistant
cancer types to the cytotoxic effects of treatment.
Furthermore, a combination of autophagy modula-
tors and conventional treatments may sensitize can-
cer cells to cancer therapies.237
Sensitization of tumor cells to therapies is one
of the most researched topics in the autophagy eld.
There is mounting preclinical evidence that target-
ing autophagy can enhance the benecial effects of
many cancer therapies. In many cancer types, inhibi-
tion of the nucleation step of autophagosome forma-
tion with type III PI3K inhibitors [e.g., 3-methylad-
enine (3-MA) or LY294002] enhances the efcacy
of chemotherapy or radiation. For example, inhibi-
tion of autophagy using 3-MA enhanced cytotoxic-
ity of radiotherapy in human esophageal squamous
carcinoma cells.238 Similarly, treatment of 3-MA
enhanced the efcacy of the Gli inhibitor GANT-61
and increased apoptotic cell death.239 Many preclini-
cal studies indicate that lysosomotropic agents (e.g.,
CQ and HCQ) prevent lysosome acidication and
block autolysosome formation, thereby augment-
ing the effect of chemotherapies and radiotherapy
on various types of cancers.237,240 For example, in
non-small-cell lung cancer, bevacizumab in com-
bination with CQ increases the efcacy of cancer
treatment.241 However, it should be noted that CQ
and HCQ are not specic autophagy inhibitors and
they may impact biological processes other than
Authophagy and Hallmarks of Cancer 257
Volume 23, Issues 5-6, 2018
autophagy. These may include lysosomal membrane
permeabilization, normalization of tumor vascula-
ture, and subsequent activation of the mitochondrial
pathway of apoptosis.242,243 Also, CQ is reported to
eliminate CSCs through autophagy-independent
pathways, including the deregulation of Janus ki-
nase 2 (JAK2)208 and the inhibition of CXCR4 and
Hedgehog signaling.244 An important limitation of
HCQ is its potency, as high doses (up to 1,200 mg
daily) generate only modest autophagy inhibition
in vivo.237 Moreover, HCQ fails to block autophagy
ux in tumor environments due to a decrease in drug
uptake by cells. Therefore, more potent and selec-
tive autophagy inhibitors are urgently needed.
A specic ATG4B inhibitor, NSC185058, has
been developed and shown to effectively inhibit
ATG4B activity and autophagy without affecting
the activities of mTOR and PI3K.245 ATG4B is a
cysteine protease that is essential for LC3 lipida-
tion and recycling.246 Inhibition of autophagy with
NSC185058 had a negative impact on the develop-
ment of Saos-2 osteosarcoma tumors in vivo.245 Ad-
ditionally, NSC185058 in combination with radio-
therapy markedly slows tumor growth and provides
survival benets in mice with intracranial glioblas-
toma xenografts.143 ATG4 proteases are emerging as
potential pharmaceutical targets for the treatment of
aggressive cancers, such as osteosarcoma and glio-
blastoma.
While signicant progress has been made with
the discovery of autophagy inhibitors in the last
decade, we must keep in mind that many of these
pharmacologic agents do not exclusively target the
autophagy pathways. Therefore, the development of
more potent and specic drugs targeting autophagy
at the preclinical stage (e.g., ATG4B inhibitors) is
highly warranted. This can help maximize the poten-
tial for autophagy manipulation in treating cancers.
VII. CONCLUSIONS
A plethora of evidence indicates the importance of
autophagy in tumor development and progression,
with both tumor-suppressive and tumor-promoting
roles. Whether autophagy modulation should be
attempted in tumor therapy remains controversial.
Nevertheless, various research groups are focusing
on therapeutically targeting autophagy in cancer.
Furthermore, many current clinical trials are using
CQ and HCQ for autophagy inhibition in combina-
tion with other therapies for cancer treatment. How-
ever, existing drugs, such as CQ, HCQ, and 3-MA
can mediate multiple effects. Thus, it is not entirely
clear that autophagy inhibition per se is solely re-
sponsible for observed therapeutic benets.247 It is
therefore important to develop more potent and se-
lective autophagy inhibitors to improve our under-
standing of autophagy and expand our therapeutic
options for multiple diseases.
CKNOWLEDGMENTSA
This work was supported by a National Institutes
of Health (NIH) grant (NS095634) to S.-Y.C.; a
Brain Cancer Research Award from the James S.
McDonnell Foundation to B.H.; NIH grants (L32
MD010147 and T32 CA070085) to A.A.A. and
(F31 CA232630) to N.S.; a Fishel Predoctoral Fel-
lowship Award from the Robert H. Lurie Compre-
hensive Cancer Center at Northwestern University
to N.S.; support from the Lou and Jean Malnati
Brain Tumor Institute at Northwestern University to
S.-Y.C. and B.H.; National Natural Science Foun-
dation of China grants (81372704, 81572467) to H.
Feng; Program for Professor of Special Appoint-
ment (Eastern Scholar) at Shanghai Institutions of
Higher Learning (2014024), Shanghai Municipal
Education Commission—Gaofeng Clinical Medi-
cine Grant Support (20161310), New Hundred Tal-
ent Program (Outstanding Academic Leader) at the
Shanghai Municipal Health Bureau (2017BR021),
and the State Key Laboratory of Oncogenes and Re-
lated Genes in China (91-17-25) to H. Feng.
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