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A simplified Bcl-2 network model reveals quantitative determinants of cell-to-cell variation in sensitivity to anti-mitotic chemotherapeutics

Kueh, Hao Yuan and Zhu, Yanting and Shi, Jue (2016) A simplified Bcl-2 network model reveals quantitative determinants of cell-to-cell variation in sensitivity to anti-mitotic chemotherapeutics. Scientific Reports, 6 . Art. No. 36585. ISSN 2045-2322. PMCID PMC5095668. https://resolver.caltech.edu/CaltechAUTHORS:20161114-121805047

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/srep36585DOIArticle
http://www.nature.com/articles/srep36585PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095668/PubMed CentralArticle
ORCID:
AuthorORCID
Kueh, Hao Yuan0000-0001-6272-6673
Additional Information:© 2016 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received: 15 June 2016; Accepted: 17 October 2016; Published online: 04 November 2016. We thank Dr. John Albeck (Systems Biology, Harvard Medical School) for the IMS-RP retroviral vector (MOMP reporter). This work was supported by the Hong Kong Research Grant Council (#261310) to J Shi. Author Contributions: H.Y.K. and J.S. designed the study; Y.Z. performed the experiments; H.Y.K. and J.S. analyzed the data; H.Y.K. performed the computational analysis; H.Y.K., Y.Z. and J.S. wrote the manuscript. The authors declare no competing financial interests.
Funders:
Funding AgencyGrant Number
Hong Kong Research Grant Council261310
PubMed Central ID:PMC5095668
Record Number:CaltechAUTHORS:20161114-121805047
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20161114-121805047
Official Citation:Kueh, H. Y. et al. A simplified Bcl-2 network model reveals quantitative determinants of cell-to-cell variation in sensitivity to anti-mitotic chemotherapeutics. Sci. Rep. 6, 36585; doi: 10.1038/srep36585 (2016)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:71994
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:15 Nov 2016 23:40
Last Modified:09 Mar 2020 13:18

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