Systems Analysis of Cancer Cell Heterogeneity in Caspase-dependent Apoptosis Subsequent to Mitochondrial Outer Membrane Permeabilization

Schmid, Jasmin; Düßmann, Heiko; Boukes, Gerhardt J.; Flanagan, Lorna; Lindner, Andreas U.; O'Connor, Carla L.; Rehm, Markus; Prehn, Jochen H.M.; Huber, Heinrich J.

doi:10.1074/jbc.m112.411827

Cited by 28 publications

(38 citation statements)

References 51 publications

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“…In this step, caspase-3 is activated either by a positive feedback loop with upstream caspase-8 (socalled type I cells) or after MOMP which is mediated by of the BCL-2 protein BID (type II cells). We further note that MOMP induces an energetic crisis caused by the loss of cytochromec, which may lead to necrosis or metabolic impairment when caspase-dependent apoptosis is blocked [21,30,31].…”

Section: Pathways Of Cardiomyocyte Apoptosis Relevant To Dox -Inducedmentioning

confidence: 81%

“…Indeed, with such quantitative signal transduction models, we were previously able to predict patient specific susceptibility to chemotherapy [31,44,54,84,85]. It is therefore expected that these models in combination with biomolecular studies that investigate molecular mediators of apoptosis can further help to identify patient more vulnerable to DOX-induced cardiac apoptosis and DCM.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, mild, non-lethal caspase-3 activity can lead to structural remodeling such as seen in other large cells [67]. As nicely shown by single cell imaging and quantitative systems biology studies of apoptosis, such sub-lethal caspase-3 activity can arise when tipping the balance for expression of proteins relevant in the post-MOMP pathway from pro-apoptotic to anti-apoptotic ones [31,68,69]. Indeed, a recent study also demonstrated that apoptosome dependent, sub-lethal caspase-activity can also lead, and even is essential, in a model of cardiomyocyte hypertrophic remodeling [70].…”

Section: Does Dox-induced Momp Render Functionally Impaired Cardiomyomentioning

confidence: 99%

“…MOMP apoptosis, APOPTO-CELL. As adaptation, we also included the pro-apoptotic protein XAF-1 which we modelled to act in the same way as SMAC, yet to be present initially in the cytosol instead of being released from the mitochondria [31,68]. As input we used gene expression data from Zhang [25] (GEO data set GSE36239).…”

Section: (Right Panel)mentioning

confidence: 99%

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Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

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The chemotherapeutic Doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10 % of pediatric cancer survivors will 10-20 years later develop severe Dilated Cardiomyopathy (DCM) and the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidences, we first argue why even little detectable apoptosis may be sufficient to cause a dilated phenotype. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream to Mitochondrial Outer Membrane Permeabilisation (MOMP). This lack of prevention of MOMP-induction then is proposed to alter the metabolic phenotype, induce hypertrophic remodeling and lead to functional cardiac impairment even in absence of cardiomyocyte apoptosis. We further discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosisprimed cancer cells and propose computational systems biology as tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM. Key messages1. Differentiated cardiomyocyte are protected to post but not pre-MOMP apoptosis 2. MOMP-induction can lead to cardiac hypertrophy and metabolic remodeling after DOX 3. DOX-exposed cardiomyocytes may be more sensitive to apoptosis over life time 4. DOX-exposed cardiomyocytes show similarities to apoptosis-primed cancer cells

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Section: Pathways Of Cardiomyocyte Apoptosis Relevant To Dox -Inducedmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Does Dox-induced Momp Render Functionally Impaired Cardiomyomentioning

confidence: 99%

Section: (Right Panel)mentioning

confidence: 99%

See 2 more Smart Citations

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Kankeu

Clarke²,

Passante

et al. 2016

J Mol Med

Self Cite

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“…Nevertheless, caspase-9 activation and apoptosis execution is highly efficient in these cells. Similar unfavorable ratios for a dimerization-based activation process were reported in various other cell lines, including MCF-7 breast cancer cells, human colon carcinoma cell lines (HCT-116, Lovo, DLD-1, HT29), and panels of 11 glioblastoma and 11 melanoma cell lines (39,40,59). Structural analysis based on electron cryo-microscopy data indicated that the seven Apaf-1 CARD domains may form a flexible procaspase-9 recruitment platform in the center of the apoptosome complex (60).…”

Section: Systems-based Evidence For Allosteric Caspase-9 Activationmentioning

confidence: 73%

A Systems Biology Analysis of Apoptosome Formation and Apoptosis Execution Supports Allosteric Procaspase-9 Activation

Würstle

Rehm

2014

Journal of Biological Chemistry

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Background: Mathematical simulations of apoptosome formation and mechanisms of caspase-9 activation were conducted and validated against experimental data. Results: Only simulations that assume allosteric caspase-9 activation can accurately reproduce all experimental data. Conclusion: A mechanism of allosteric caspase-9 activation is favored over homodimerization-based activation. Significance: Our findings challenge the dogma that all initiator caspases are activated by homodimerization.

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Cancer Systems Biology: Current Achievements in – Omics Data Analysis, Network Reconstruction and Mathematical Modelling

Vera

Schmitz

2014

Encyclopedia of Life Sciences

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Systems biology is a multidisciplinary methodology in which quantitative biological experimental data are dissected using mathematical modelling and other computational and network biology tools, aiming at understanding the structure, function and dynamical regulation of biochemical networks. Systems biology will play a major role in the future molecular and clinical oncology because (a) it can be used for the analysis of cancer‐relevant high‐throughput data, (b) it provides tools for the reconstruction of the large multilevel regulatory networks that govern critical cancer phenotypes and (c) it is necessary when investigating cancer‐relevant networks holding multiple overlapping nonlinear regulatory motifs like feedback and feedforward loops. Here, the value of the systems biology approach in handling cancer genomics and transcriptomics data, the reconstruction of cancer networks and the use of mathematical modelling in the elucidation of cancer networks as well as in the design of anticancer therapies are discusses. Some recent case studies as proof of principle are highlighted. Key Concepts: Systems biology is a multidisciplinary approach that involves the analysis of quantitative experimental data via mathematical modelling and computational and network biology. Modelling of cancer‐related networks is necessary because these networks display multiple nonlinear regulatory motifs like feedback loops. Mathematical models have been used to elucidate the structure, dynamics, dysregulation and crosstalk of cancer pathways like the JAK/STAT, p53, MAPK, NFkB and intrinsinc/extrinsic apoptosis signalling pathways, as well as in microRNA cancer regulation. Multi‐scale mathematical models can accurately describe the spatial configuration of tumours, their crosstalk with the surrounding microenvironment and their role in physiological mechanisms like angiogenesis and immune system response. Mathematical modelling has been used to assess and personalise conventional anticancer therapies, but it is also used in the detection of new anticancer drug targets and the development of combined or immune therapies. Cancer bioinformatics facilitates efficient analyses and integration of diverse types of biomedical high‐throughput data for the elucidation of causes of tumour initiation, progression and metastasis but also for the management, storage and exchange of experimental and clinical data. Cancer systems biology integrates algorithms, methodologies, software tools and web resources into customised analysis workflows to explore and understand the molecular mechanisms underlying this complex disease. Data integration and analysis is used to identify novel robust and precise biomarkers, to identify network biomarkers and to design individual patient‐tailored therapeutic interventions.

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Systems Analysis of Cancer Cell Heterogeneity in Caspase-dependent Apoptosis Subsequent to Mitochondrial Outer Membrane Permeabilization

Cited by 28 publications

References 51 publications

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

A Systems Biology Analysis of Apoptosome Formation and Apoptosis Execution Supports Allosteric Procaspase-9 Activation

Cancer Systems Biology: Current Achievements in – Omics Data Analysis, Network Reconstruction and Mathematical Modelling

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