Mathematical modelling of the mitochondrial apoptosis pathway

Huber, Heinrich J.; Duessmann, Heiko; Wenus, Jakub; Kilbride, Seán M.; Prehn, Jochen H.M.

doi:10.1016/j.bbamcr.2010.10.004

Cited by 24 publications

(18 citation statements)

References 76 publications

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“…MOMP was assumed to occur when homo-oligomers larger than or equal to hexamers (further denoted as pores; ref. 26) bound more than 10% of total effectors (12). The antiapoptotic proteins BCL2, BCL(X)L, and MCL1 were modeled to attenuate MOMP by engaging the BH3-only proteins and effectors.…”

Section: Resultsmentioning

confidence: 99%

“…However, the complexity of the interaction of antagonizing BCL2 family proteins makes it unlikely that mutations or deregulation of single apoptosisrelated proteins are sufficient to characterize apoptosis execution or its impairment in patients. Therefore, holistic approaches studying the interplay of several proteins and including quantitative protein levels and interaction kinetics may be of significant interest (12)(13)(14)(15)(16). However, no model of BCL2 interaction and MOMP execution has yet been transferred into a clinical setting.…”

Section: Introductionmentioning

confidence: 99%

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Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy

et al. 2013

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Apoptotic desensitization is a hallmark of cancer cells, but present knowledge of molecular systems controlling apoptosis has yet to provide significant prognostic insights. Here, we report findings from a systems study of the intrinsic pathway of apoptosis by BCL2 family proteins and clinical translation of its findings into a model with applications in colorectal cancer (CRC). By determining absolute protein quantifications in CRC cells and patient tumor samples, we found that BAK and BAX were expressed more highly than their antiapoptotic inhibitors. This counterintuitive finding suggested that sole inhibition of effector BAX and BAK could not be sufficient for systems stability in nonstressed cells. Assuming a model of direct effector activation by BH3-only proteins, we calculated that the amount of stress-induced BH3-only proteins required to activate mitochondrial apoptosis could predict individual death responses of CRC cells to 5-fluorouracil/oxaliplatin. Applying this model predictor to protein profiles in tumor and matched normal tissue samples from 26 patients with CRCs, we found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. In addition, these differences were sufficient to differentiate clinical responders from nonresponders with high confidence. Applications of our model, termed DR_MOMP, were used to assess the impact of apoptosis-sensitizing dugs in lowering the necessary dose of state-of-the-art chemotherapy in individual patients. Together, our findings offer a ready clinical tool with the potential to tailor chemotherapy to individual patients. Cancer Res; 73(2); 519-28. Ó2012 AACR.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy

et al. 2013

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“…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%

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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“…Heterogeneity and Robustness of Apoptosis Caused by Fluctuations in Enzymatic Activities-Kinetic parameters are factors that relate the speed of a chemical reaction to the concentrations of the reaction partners and therefore are a means to quantify reaction speed of chemical reactions (8). Kinetic parameters are assumed in APOPTO-CELL to describe enzymatic cleavage or enzyme inhibition (17).…”

Section: Apoptosis Can Be Impaired Subsequent To Momp and Can Be Explmentioning

confidence: 99%

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

Schmid

Düßmann

Boukes

et al. 2012

Journal of Biological Chemistry

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Background: Computational systems models may allow understanding of progression and impairment of apoptosis based on quantitative protein profiles. Results: We found apoptosis to be impaired in some cell lines after MOMP, which can be understood by our systems model "APOPTO-CELL". Conclusion: APOPTO-CELL helps to understand heterogeneity in apoptosis execution after MOMP. Significance: APOPTO-CELL may help to assess cancer-specific efficacy of chemotherapeutics that induce apoptosis.

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Mathematical modelling of the mitochondrial apoptosis pathway

Cited by 24 publications

References 76 publications

Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy

Systems Analysis of BCL2 Protein Family Interactions Establishes a Model to Predict Responses to Chemotherapy

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

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

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