A simplified Bcl-2 network model reveals quantitative determinants of cell-to-cell variation in sensitivity to anti-mitotic chemotherapeutics.
Sci Rep
; 6: 36585, 2016 11 04.
Article
em En
| MEDLINE
| ID: mdl-27811996
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas c-bcl-2
/
Antimitóticos
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Mitose
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Antineoplásicos
Tipo de estudo:
Diagnostic_studies
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Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
ENGLAND
/
ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
/
REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM