Huang Shan, Tang Rui, Poon Randy Y C
Division of Life Science, Center for Cancer Research, and State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong.
Oncotarget. 2016 Jun 21;7(25):38718-38730. doi: 10.18632/oncotarget.9586.
Microtubule inhibitors including taxanes and vinca alkaloids are among the most widely used anticancer agents. Disrupting the microtubules activates the spindle-assembly checkpoint and traps cells in mitosis. Whether cells subsequently undergo mitotic cell death is an important factor for the effectiveness of the anticancer agents. Given that apoptosis accounts for the majority of mitotic cell death induced by microtubule inhibitors, we performed a systematic study to determine which members of the anti-apoptotic BCL-2 family are involved in determining the duration of mitotic block before cell death or slippage. Depletion of several anti-apoptotic BCL-2-like proteins significantly shortened the time before apoptosis. Among these proteins, BCL-W has not been previously characterized to play a role in mitotic cell death. Although the expression of BCL-W remained constant during mitotic block, it varied significantly between different cell lines. Knockdown of BCL-W with siRNA or disruption of the BCL-W gene with CRISPR-Cas9 speeded up mitotic cell death. Conversely, overexpression of BCL-W delayed mitotic cell death, extending the mitotic block to allow mitotic slippage. Taken together, these results showed that BCL-W contributes to the threshold of anti-apoptotic activity during mitosis.
包括紫杉烷类和长春花生物碱在内的微管抑制剂是使用最广泛的抗癌药物之一。破坏微管会激活纺锤体组装检查点并使细胞停滞在有丝分裂期。细胞随后是否经历有丝分裂细胞死亡是抗癌药物有效性的一个重要因素。鉴于凋亡是微管抑制剂诱导的有丝分裂细胞死亡的主要形式，我们进行了一项系统研究，以确定抗凋亡BCL-2家族的哪些成员参与决定细胞死亡或脱离之前有丝分裂阻滞的持续时间。几种抗凋亡BCL-2样蛋白的缺失显著缩短了凋亡前的时间。在这些蛋白中，BCL-W以前尚未被证实参与有丝分裂细胞死亡。虽然在有丝分裂阻滞期间BCL-W的表达保持恒定，但在不同细胞系之间差异很大。用小干扰RNA（siRNA）敲低BCL-W或用CRISPR-Cas9破坏BCL-W基因会加速有丝分裂细胞死亡。相反，BCL-W的过表达会延迟有丝分裂细胞死亡，延长有丝分裂阻滞时间以允许有丝分裂脱离。综上所述，这些结果表明BCL-W有助于在有丝分裂期间抗凋亡活性的阈值。
