Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers
Bennett, A, Sloss, O, Topham, CH, Nelson, L, Tighe, A and Taylor, SS 2016, 'Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers' , Open Biology .
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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.
|Schools:||Schools > School of Environment and Life Sciences > Biomedical Research Centre|
|Journal or Publication Title:||Open Biology|
|Publisher:||The Royal Society Publishing|
|Funders:||Cancer Research UK, Medical Research Council (MRC), Wellcome Trust, University of Manchester Presidential Scholarship|
|Depositing User:||CH Topham|
|Date Deposited:||01 Sep 2016 08:39|
|Last Modified:||01 Sep 2016 08:39|
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