A simplified Bcl-2 network model reveals quantitative determinants of cell-to-cell variation in sensitivity to anti-mitotic chemotherapeutics.
Anti-mitotic drugs constitute a major class of cytotoxic chemotherapeutics used in the clinic, killing cancer cells by inducing prolonged mitotic arrest that activates intrinsic apoptosis. Anti-mitotics-induced apoptosis is known to involve degradation of anti-apoptotic Bcl-2 proteins during mitotic arrest; however, it remains unclear how this mechanism accounts for significant heterogeneity observed in the cell death responses both within and between cancer cell types. To unravel quantitative determinants underlying variability in anti-mitotic drug response, we constructed a single-cell dynamical Bcl-2 network model describing cell death control during mitotic arrest, and constrained the model using experimental data from four representative cancer cell lines. The modeling analysis revealed that, given a variable, slowly accumulating pro-apoptotic signal arising from anti-apoptotic protein degradation, generation of a switch-like apoptotic response requires formation of pro-apoptotic Bak complexes with hundreds of subunits, suggesting a crucial role for high-order cooperativity. Moreover, we found that cell-type variation in susceptibility to drug-induced mitotic death arises primarily from differential expression of the anti-apoptotic proteins Bcl-xL and Mcl-1 relative to Bak. The dependence of anti-mitotic drug response on Bcl-xL and Mcl-1 that we derived from the modeling analysis provides a quantitative measure to predict sensitivity of distinct cancer cells to anti-mitotic drug treatment.
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.|Center for Quantitative Systems Biology, Hong Kong Baptist University, Hong Kong, China.
Hao Yuan
HY
Kueh
Center for Quantitative Systems Biology, Hong Kong Baptist University, Hong Kong, China.|Department of Physics and Department of Biology, Hong Kong Baptist University, Hong Kong, China.
Yanting
Y
Zhu
Center for Quantitative Systems Biology, Hong Kong Baptist University, Hong Kong, China.|Department of Physics and Department of Biology, Hong Kong Baptist University, Hong Kong, China.
Jue
J
Shi
D000072283:A549 Cells; D050256:Antimitotic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein