Bcl-xL controls a switch between cell death modes during mitotic arrest.

摘要: Antimitotic agents such as microtubule inhibitors (paclitaxel) are widely used in cancer therapy while new blocking mitosis onset currently development. All these impose a prolonged mitotic arrest cells that relies on sustained activation of the spindle assembly checkpoint and may lead to subsequent cell death by incompletely understood molecular events. We have investigated role played anti-apoptotic Bcl-2 family members fate mitotically arrested mammary tumor treated with paclitaxel, or depleted Cdc20, activator anaphase promoting complex. Under conditions, weak delayed occurs is caspase- Bax/Bak-independent. Moreover, BH3 profiling assays indicate viable during primed die apoptosis Bcl-xL required maintain mitochondrial integrity. Consistently, depletion, treatment its inhibitor ABT-737 (but not specific ABT-199), converts response antimitotics efficient caspase Bax-dependent apoptosis. Apoptotic priming under conditions relies, at least part, phosphorylation serine 62 Bcl-xL, which modulates interaction Bax sensitivity ABT-737. The phospho-mimetic S62D-Bcl-xL mutant indeed less than corresponding phospho-deficient S62A-Bcl-xL sequestrating protecting from yeast Bax-induced growth inhibition. Our results provide rationale for combining targeting antimitotic improve clinical efficacy strategy therapy.