Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers

Bennett, A; Sloss, O; Topham, CH; Nelson, L; Tighe, A; Taylor, SS

Abstract

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

Bennett, A., Sloss, O., Topham, C., Nelson, L., Tighe, A., & Taylor, S. (2016). Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers. Open Biology, 6(8), https://doi.org/10.1098/rsob.160134

• Journal Article Type: Article
• Acceptance Date: Jul 8, 2016
• Online Publication Date: Aug 1, 2016
• Publication Date: Aug 1, 2016
• Deposit Date: Sep 1, 2016
• Publicly Available Date: Sep 1, 2016
• Journal: Open Biology
• Publisher: The Royal Society
• Volume: 6
• Issue: 8
• DOI: https://doi.org/10.1098/rsob.160134
• Publisher URL: http://dx.doi.org/10.1098/rsob.160134
• Related Public URLs: http://rsob.royalsocietypublishing.org/
• Additional Information: Grant Number: MR/L006839/1