Inna N LavrikOtto-von-Guericke-Universität Magdeburg | OvGU · Translational Inflammation Research
Inna N Lavrik
Professor
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221
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Introduction
Skills and Expertise
Publications
Publications (221)
Procaspase-8 is a key mediator of death receptor (DR)-mediated pathways. Recently, the role of post-translational modifications (PTMs) of procaspase-8 in controlling cell death has received increasing attention. Here, using mass spectrometry screening, pharmacological inhibition and biochemical assays, we show that procaspase-8 can be targeted by t...
Malignant melanoma (MM) is known to be intrinsically chemoresistant, even though only ~20% of MM carry mutations of the tumor suppressor p53. Despite improvement of systemic therapy the mortality rate of patients suffering from metastatic MM is still ~70%, highlighting the need for alternative treatment options or for the re-establishment of conven...
Hepatocellular carcinoma (HCC) is a common severe type of liver cancer characterized by an extremely aggressive course and low survival rates. It is known that disruptions in the regulation of apoptosis activation are some of the key features inherent in most cancer cells, which determines the pharmacological induction of apoptosis as an important...
RL2 (recombinant lactaptin 2), a recombinant analogon of the human milk protein Κ-Casein, induces mitophagy and cell death in breast carcinoma cells. Furthermore, RL2 was shown to enhance extrinsic apoptosis upon long-term treatment while inhibiting it upon short-term stimulation. However, the effects of RL2 on the action of chemotherapeutic drugs...
Hepatocellular carcinoma (HCC) has been associated with hepatitis C viral (HCV) infection as a potential risk factor. Nonetheless, the precise genetic regulatory mechanisms triggered by the virus, leading to virus-induced hepatocarcinogenesis, remain unclear. We hypothesized that HCV proteins might modulate the activity of aberrantly methylated HCC...
One of the most common malignant liver diseases is hepatocellular carcinoma, which has a high recurrence rate and a low five-year survival rate. It is very heterogeneous both in structure and between patients, which complicates the diagnosis, prognosis and response to treatment. In this regard, an individualized, patient-centered approach becomes i...
One of the most common malignant liver diseases is hepatocellular carcinoma, which has a high recurrence rate and a low five-year survival rate. It is very heterogeneous both in structure and between patients, which complicates diagnosis, prognosis and response to treatment. In this regard, an individualized, patient-centered approach becomes impor...
Hepatitis C virus (HCV) is a risk factor that leads to hepatocellular carcinoma (HCC) development. Epigenetic changes are known to play an important role in the molecular genetic mechanisms of virus-induced oncogenesis. Aber rant DNA methylation is a mediator of epigenetic changes that are closely associated with the HCC pathogenesis and considered...
Breast cancer is still the most common cancer in women worldwide. Resistance to drugs and recurrence of the disease are two leading causes of failure in treatment. For a more efficient treatment of patients, the development of novel therapeutic regimes is needed. Recent studies indicate that modulation of autophagy in concert with apoptosis inducti...
CD95/Fas/APO-1 can trigger apoptotic as well as nonapoptotic pathways in immune cells. CD95 signaling in humans can be inhibited by several mechanisms, including mutations in the gene encoding CD95. CD95 mutations lead to autoimmune disorders, such as autoimmune lymphoproliferative syndrome (ALPS). Gaining further insight into the reported mutation...
The extrinsic pathway is mediated by death receptors (DRs), including CD95 (APO-1/Fas) or TRAILR-1/2. Defects in apoptosis regulation lead to cancer and other malignancies. The master regulator of the DR networks is the cellular FLICE inhibitory protein (c-FLIP). In addition to its key role in apoptosis, c-FLIP may exert other cellular functions, i...
The naked mole rat (NMR), Heterocephalus glaber, is the longest-living rodent species, and is extraordinarily resistant to cancer and aging-related diseases. The molecular basis for these unique phenotypic traits of the NMR is under extensive research. However, the role of regulated cell death (RCD) in the longevity and the protection from cancer i...
A recombinant fragment of human κ-Casein, termed RL2, induces cell death of breast cancer cells; however, molecular mechanisms of RL2-mediated cell death have remained largely unknown. In the current study, we have decoded the molecular mechanism of the RL2-mediated cell death and found that RL2 acts via the induction of mitophagy. This was monitor...
The development of efficient combinatorial treatments is one of the key tasks in modern anti-cancer therapies. An apoptotic signal can either be induced by activation of death receptors (DR) (extrinsic pathway) or via the mitochondria (intrinsic pathway). Cancer cells are characterized by deregulation of both pathways. Procaspase-8 activation in ex...
Procaspase-8 activation at the death-inducing signaling complex (DISC) triggers extrinsic apoptotic pathway. Procaspase-8 activation takes place in the death effector domain (DED) filaments and is regulated by c-FLIP proteins, in particular, by the long isoform c-FLIPL. Recently, the first-in-class chemical probe targeting the caspase-8/c-FLIPL het...
Cell fate decisions regulating survival and death are essential for maintaining tissue homeostasis; dysregulation thereof can lead to tumor development. In some cases, survival and death are triggered by the same receptor, e.g., tumor necrosis factor (TNF)-receptor 1 (TNFR1). We identified a prominent role for the cold shock Y-box binding protein-1...
Breast cancer is still one of the most common cancers for women. Specified therapeutics
are indispensable for optimal treatment. In previous studies, it has been shown that RL2, the
recombinant fragment of human κ-Casein, induces cell death in breast cancer cells. However, the
molecular mechanisms of RL2-induced cell death remain largely unknown. I...
Apoptosis is a form of programmed cell death, deregulation of which occurs in multiple disorders, including neurodegenerative and autoimmune diseases as well as cancer. The formation of a death-inducing signaling complex (DISC) and death effector domain (DED) filaments are critical for initiation of the extrinsic apoptotic pathway. Post-translation...
The assembly of the death-inducing signaling complex (DISC) and death effector domain (DED) filaments at CD95/Fas initiates extrinsic apoptosis. Procaspase-8 activation at the DED filaments is controlled by short and long c-FLIP isoforms. Despite apparent progress in understanding the assembly of CD95-activated platforms and DED filaments, the deta...
Pharmacological targeting via small molecule-based chemical probes has recently acquired an emerging importance as a valuable tool to delineate molecular mechanisms. Induction of apoptosis via CD95/Fas and TRAIL-R1/2 is triggered by the formation of the death-inducing signaling complex (DISC). Caspase-8 activation at the DISC is largely controlled...
Initiation of apoptosis by chemotherapeutic drugs is one of the most effective approaches to the treatment of cancers. Caspases, the main enzymes of apoptosis, undergo activation to initiate cell death. Activation of initiator caspases requires their binding to special protein complexes. For elucidation of the mechanisms of apoptosis, these complex...
Caspase-8 performs initiatory functions during the induction of apoptosis through the extrinsic pathway. Apoptosis is a type of programmed cell death that plays an important role in regulating embryogenesis and maintaining homeostasis in the tissue of an adult organism, as well as differentiating and removing damaged cells. Dysregulation of the apo...
Cytopoxic effect of RL2 lactaptin (the recombinant analog of proteolytic fragment of human kappa‐casein) toward tumor cells in vitro and in vivo presents it as a novel promising antitumor drug. Binding of any drugs with serum proteins can affect their activity, distribution, rate of excretion, and toxicity of pharmaceutical agent in the human body....
Autophagy is a degradative process in which cellular organelles and proteins are recycled to restore homeostasis and cellular metabolism. Autophagy can be either a prosurvival or a prodeath process and remains one of the most fundamental processes for cell vitality. Thus autophagy modulation is an important approach for reinforcement anticancer the...
CD95 is a member of the death receptor family and is well-known to promote apoptosis. However, accumulating evidence indicates that in some context CD95 has not only the potential to induce apoptosis but also can trigger non-apoptotic signal leading to cell survival, proliferation, cancer growth and metastasis. Despite extensive investigations focu...
Background:
Structural homology modeling supported by bioinformatics analysis plays a key role in uncovering new molecular interactions within gene regulatory networks. Here, we have applied this powerful approach to analyze the molecular interactions orchestrating death receptor signaling networks. In particular, we focused on the molecular mecha...
Background
Currently, more than 150 million people worldwide suffer from lymphedema. It is a chronic progressive disease characterized by high-protein edema of various parts of the body due to defects in lymphatic drainage. Molecular-genetic mechanisms of the disease are still poorly understood. Beginning of a clinical manifestation of primary lymp...
Mutations of fms‐like tyrosine kinase 3 (FLT3) are the most frequent mutations in acute myeloid leukemia (AML). Furthermore, the internal tandem duplication (ITD) represents the most common mutation of FLT3 in AML. To explore therapeutic strategies for AML patients carrying FLT3‐ITD, we analyzed death receptor (DR) signaling networks in AML cells c...
Glycosylation and glycan-binding proteins such as galectins play an important role in the control of cell death signaling. Strikingly, very little attention has been given so far to the understanding of the molecular details behind this key regulatory network. Glycans attached to the death receptors such as CD95 and TRAIL-Rs, either alone or in a c...
CD95/Fas/APO-1 is a member of the death receptor family that triggers apoptotic and anti-apoptotic responses in particular, NF-κB. These responses are characterized by a strong heterogeneity within a population of cells. To determine how the cell decides between life and death we developed a computational model supported by imaging flow cytometry a...
Overview of reaction network.
(EPS)
Imaging flow cytometry analysis of CD95 signaling in HeLa-CD95 cells.
(A) Gating strategy for imaging flow cytometry experiments shown for stimulation of HeLa-CD95 cells with 250 ng/ml CD95L followed by staining with anti-p65 antibodies as well as of the nucleus with the DNA dye 7AAD. For subsequent analysis, focused images of single cells are sele...
The analysis of CD95 DISC formation in HeLa-CD95 cells.
(A) HeLa-CD95 cells were stimulated with 250 ng/ml or 500 ng/ml CD95L for 20, 40 or 60 minutes. Cells lysates were used for immunoprecipitation (IP) with anti-APO-1 antibody. Cell lysates and IPs were analyzed with western blot and indicated antibodies. The right part of the figure is shown in...
Model calibration with the imaging flow cytometry data for NF-κB translocation to the nucleus.
Experimental data (red) and simulations (blue) of NF-κB activation for HeLa-CD95 cells stimulated with indicated concentrations of CD95L and for indicated time intervals.
(PDF)
r Means and standard deviations of p43-FLIP and NF-κB.
(A) Standard deviation of p43-FLIP corresponding to Fig 4B. (B) Means and standard deviations of p43-FLIP upon consideration of both intrinsic and extrinsic noises. (C) Investigation of the impact of different initial conditions of nuclear NF-κB (1/1000, 1/100, 1/10 of the total cellular amount...
Live cell imaging of HeLa-CD95 cells upon CD95L stimulation and addition of inhibitors of apoptosis and NF-kB pathways.
(A) HeLa-CD95 cells were pre-incubated with 10 μM IKK inhibitor VII or 50 μM zVAD-fmk for 30 minutes and stimulated with 5 ng/ml CD95L for indicated time intervals. Caspase-3/7 activity was monitored with IncuCyte and IncuCyte Cas...
Sensitivity analysis of the TOS/TOD ratio.
Sensitivity analysis of the TOS/TOD ratio in regard to the model rate constants (low stimulation doses). The rate constants are numbered according to S2 Table.
(EPS)
HeLa-CD95 cells were stimulated with 5 ng/ml CD95L for displayed time plus 30 minutes.
Caspase-3/7 activity was monitored with IncuCyte and IncuCyte Caspase-3/7 Apoptosis Assay Reagent. Purple cells are positive for caspase-3/7 activity.
(AVI)
List of species used in the model topology.
(EPS)
Analysis of CD95-induced caspase and NF-κB activation.
(A) Scheme of the CD95/Fas signaling pathway, procaspase-8 and c-FLIP cleavage products. (B) HeLa-CD95 cells were stimulated with 250 ng/ml of CD95L for indicated time intervals with or without preincubation with zVAD-fmk; and subsequently analysed by western blot using the indicated antibodies...
Model calibration with the imaging flow cytometry data for caspase-3 activation.
Experimental data (red) and simulations (blue) of caspase-3 activation for HeLa-CD95 cells stimulated with indicated concentrations of CD95L and for indicated time intervals.
(PDF)
Confidence interval of the critical TOS/TOD ratio.
The optimal value of rcrit is marked with a circle. Only rcrit values below the constant line are located in the 0.95 confidence interval.
(EPS)
Modeling procedures.
(PDF)
HeLa-CD95 cells were pre-incubated with 10 μM IKK inhibitor VII for 30 minutes and stimulated with 5 ng/ml CD95L for displayed time plus 30 minutes.
Caspase-3/7 activity was monitored with IncuCyte and IncuCyte Caspase-3/7 Apoptosis Assay Reagent. Purple cells are positive for caspase-3/7 activity.
(AVI)
HeLa-CD95 cells were pre-incubated with 50 μM zVAD-fmk for 30 minutes and stimulated with 5 ng/ml CD95L for displayed time plus 30 minutes.
Caspase-3/7 activity was monitored with IncuCyte and IncuCyte Caspase-3/7 Apoptosis Assay Reagent. Purple cells are positive for caspase-3/7 activity.
(AVI)
Apoptosis model in SBML format.
(XML)
Experimental western blot data used for the model calibration.
HeLa-CD95 cells were stimulated with 250 ng/ml CD95L for indicated times. Western blot analysis was performed with the indicated antibodies, quantified and used for the calibration of the model.
(PDF)
Estimating the critical amount of caspase-3.
The distribution of viable (green, unstimulated) and apoptotic (red, 15h after stimulation with 50 ng/ml CD95L) cells regarding the caspase-3 fluorescence can be approximated by normal distributions, which differ in mean and variance. By applying a quadratic discriminant analysis the intersection point (...
Sensitivity analysis of the TOS/TOD ratio.
Sensitivity analysis of the TOS/TOD ratio in regard to the model rate constants (high stimulation doses). The rate constants are numbered according to S2 Table.
(EPS)
Programmed cell death is governed by a set of gene networks, which define a variety of distinct molecular mechanisms essential for the maintenance of multicellular organisms. The most studied modality of programmed cell death is known as apoptosis. Caspase-2, as a member of the family of the cysteine-dependent protease, demonstrates both proapoptot...
The cleavage of nuclear proteins by caspases promotes nuclear breakdown and, therefore, plays a key role in apoptosis execution. However, the detailed molecular mechanisms of these events remain unclear. To get more insights into the mechanisms of nuclear events during apoptosis we set up a rapid fractionation protocol for the separation of the cyt...
Imaging flow cytometry is a powerful experimental technique combining the strength of microscopy and flow cytometry to enable high-throughput characterization of cell populations on a detailed microscopic scale. This approach has an increasing importance for distinguishing between different cellular phenotypes such as proliferation, cell division a...
Supplementary material containing detailed discussions and further information regarding our approach.
(PDF)
Parkinson's disease (PD) affects an estimated 7-10 million people worldwide and 210 000 people in Russia. PD is accompanied by degeneration of dopaminergic neurons and because of that neuronal apoptosis is an important factor in this disease. Analysis of gene networks is one of the key approaches in systems biology. We previously developed the ANDS...
Background
Hypertension and bronchial asthma are a major issue for people’s health. As of 2014, approximately one billion adults, or ~ 22% of the world population, have had hypertension. As of 2011, 235–330 million people globally have been affected by asthma and approximately 250,000–345,000 people have died each year from the disease. The develop...
Background:
The development of approaches that increase therapeutic effects of anti-cancer drugs is one of the most important tasks of oncology. Caloric restriction in vivo or serum deprivation (SD) in vitro has been shown to be an effective tool for sensitizing cancer cells to chemotherapeutic drugs. However, the detailed mechanisms underlying th...
Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic...
Glaucoma is a chronic progressive disease. It involves more than 60 million people worldwide. Primary open-angle glaucoma (POAG) is one of its commonest forms. About 2.71 million people in the United States suffered from POAG in 2011. Currently, POAG is a major cause of irreversible vision loss. The risk of blindness in patients with treated open-a...
The human pathogen Helicobacter pylori infects more than half of the world's population and is a paradigm for persistent yet asymptomatic infection but increases the risk for chronic gastritis and gastric adenocarcinoma. For successful colonization, H. pylori needs to subvert the host cell death response, which serves to confine pathogen infection...
Apoptosis is a crucial program of cell death that controls development and homeostasis of multicellular organisms. The main initiators and executors of this process are the Cysteine-dependent ASPartate proteASES - caspases. A number of regulatory circuits tightly control caspase processing and activity. One of the most important, yet, at the same t...
Apoptosis or programmed cell death is important for multicellular organisms to keep cell homeostasis and for the clearance of mutated or infected cells. Apoptosis can be induced by intrinsic or extrinsic stimuli. The first event in extrinsic apoptosis is the formation of the Death-Inducing Signalling Complex (DISC), where the initiator caspases-8 a...
