Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers.
Affiliation
Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4QLIssue Date
2016-08
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Cell fate in response to an aberrant mitosis is governed by two competing networks: the spindle assembly checkpoint (SAC) and the intrinsic apoptosis pathway. The mechanistic interplay between these two networks is obscured by functional redundancy and the ability of cells to die either in mitosis or in the subsequent interphase. By coupling time-lapse microscopy with selective pharmacological agents, we systematically probe pro-survival Bcl-xL in response to various mitotic perturbations. Concentration matrices show that BH3-mimetic-mediated inhibition of Bcl-xL synergises with perturbations that induce an SAC-mediated mitotic block, including drugs that dampen microtubule dynamics, and inhibitors targeting kinesins and kinases required for spindle assembly. By contrast, Bcl-xL inhibition does not synergize with drugs which drive cells through an aberrant mitosis by overriding the SAC. This differential effect, which is explained by compensatory Mcl-1 function, provides opportunities for patient stratification and combination treatments in the context of cancer chemotherapy.Citation
Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers. 2016, 6 (8): Open BiolJournal
Open BiologyDOI
10.1098/rsob.160134PubMed ID
27512141Type
ArticleLanguage
enISSN
2046-2441ae974a485f413a2113503eed53cd6c53
10.1098/rsob.160134
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