title: Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers.
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.
authors: Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4QL, UK.
authors: Ailsa
authors: A
authors: Bennett
authors: Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4QL, UK.
authors: Olivia
authors: O
authors: Sloss
authors: Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4QL, UK.
authors: Caroline
authors: C
authors: Topham
authors: Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4QL, UK.
authors: Louisa
authors: L
authors: Nelson
authors: Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4QL, UK.
authors: Anthony
authors: A
authors: Tighe
authors: Manchester Cancer Research Centre, University of Manchester, Wilmslow Road, Manchester M20 4QL, UK stephen.taylor@manchester.ac.uk.
authors: Stephen S
authors: 0000-0003-4621-9326
authors: SS
authors: Taylor
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: C494811:BCL2L1 protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D054852:Small Molecule Libraries; D050257:Tubulin Modulators; D051020:bcl-X Protein; D017239:Paclitaxel; D015739:Nocodazole
keywords: WEHI-539; apoptosis; paclitaxel; spindle checkpoint; taxol