Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers.
Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers.
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DOI：
10.1098/rsob.160134
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发表时间：
2016-08
期刊：
影响因子：
5.8
通讯作者：
Taylor SS
中科院分区：
文献类型：
--
作者：
Bennett A;Sloss O;Topham C;Nelson L;Tighe A;Taylor SS
细胞命运对异常有丝分裂的反应是由两个相互竞争的网络控制的：纺锤体组装检查点（SAC）和内在凋亡途径。这两个网络之间的机制相互作用被功能冗余和细胞在有丝分裂或随后的间期死亡的能力所掩盖。通过将延时显微镜与选择性药物相结合，我们系统地探测了对各种有丝分裂扰动的促生存Bcl-xL。浓度矩阵显示bh3模拟物介导的Bcl-xL抑制与诱导sac介导的有丝分裂阻断的扰动协同作用，包括抑制微管动力学的药物，以及针对纺锤体组装所需的激酶和激酶的抑制剂。相比之下，Bcl-xL抑制不与药物协同作用，这些药物通过覆盖SAC来驱动细胞进行异常有丝分裂。这种差异效应可以用代偿性Mcl-1功能来解释，为癌症化疗背景下的患者分层和联合治疗提供了机会。
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.
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