Depletion of Survivin suppresses docetaxel-induced apoptosis in HeLa cells by facilitating mitotic slippage.
Depletion of Survivin suppresses docetaxel-induced apoptosis in HeLa cells by facilitating mitotic slippage.
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DOI：
10.1038/s41598-021-81563-3
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发表时间：
2021-01-27
影响因子：
4.6
通讯作者：
Jiang ZX
中科院分区：
文献类型：
--
作者：
Han TL;Sha H;Ji J;Li YT;Wu DS;Lin H;Hu B;Jiang ZX
紫杉烷类的抗癌作用归因于通过激活纺锤体组装检查点诱导有丝分裂停滞。延长有丝分裂停滞后的细胞死亡是由内在细胞凋亡途径介导的。因此，影响有丝分裂停滞的稳健性或破坏细胞凋亡机制的因素会赋予耐药性。 Survivin 是一种凋亡蛋白抑制剂。它的过度表达与化疗耐药相关，其靶向导致药物敏化。然而，Survivin 还专门作用于对紫杉烷类药物的纺锤体组装检查点反应。因此，生存素耗尽的细胞未能阻止有丝分裂可能导致紫杉烷抗性。在这里，我们发现 Survivin 耗竭可通过促进有丝分裂滑动来保护 HeLa 细胞免受多西紫杉醇诱导的细胞凋亡。然而，生存素消耗不会促进肿瘤细胞的克隆存活，但会增加多西紫杉醇诱导的细胞衰老水平。此外，与抗凋亡 Bcl-xL 或 Bcl-2 相比，Survivin 的慢病毒过表达不能提供针对多西紫杉醇或顺铂治疗的保护。我们的研究结果表明，靶向生存素可能通过驱动细胞异常有丝分裂进展来影响细胞对多西紫杉醇的反应，而不是直接使细胞对细胞凋亡敏感。
The anticancer effects of taxanes are attributed to the induction of mitotic arrest through activation of the spindle assembly checkpoint. Cell death following extended mitotic arrest is mediated by the intrinsic apoptosis pathway. Accordingly, factors that influence the robustness of mitotic arrest or disrupt the apoptotic machinery confer drug resistance. Survivin is an inhibitor of apoptosis protein. Its overexpression is associated with chemoresistance, and its targeting leads to drug sensitization. However, Survivin also acts specifically in the spindle assembly checkpoint response to taxanes. Hence, the failure of Survivin-depleted cells to arrest in mitosis may lead to taxane resistance. Here we show that Survivin depletion protects HeLa cells against docetaxel-induced apoptosis by facilitating mitotic slippage. However, Survivin depletion does not promote clonogenic survival of tumor cells but increases the level of cellular senescence induced by docetaxel. Moreover, lentiviral overexpression of Survivin does not provide protection against docetaxel or cisplatin treatment, in contrast to the anti-apoptotic Bcl-xL or Bcl-2. Our findings suggest that targeting Survivin may influence the cell response to docetaxel by driving the cells through aberrant mitotic progression, rather than directly sensitizing cells to apoptosis.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
6
作者：
Masuda, A;Maeno, K;Takahashi, T
通讯作者：
Takahashi, T
DOI：
10.1073/pnas.0401142101
发表时间：
2004-06-08
影响因子：
11.1
作者：
Kops, GJPL;Foltz, DR;Cleveland, DW
通讯作者：
Cleveland, DW
影响因子：
12.4
作者：
Carlotti, F;Bazuine, M;Hoeben, RC
通讯作者：
Hoeben, RC
小分子黄质蛋白揭示了Aurora B在校正动型微管附着和维持纺锤体组装检查点方面的作用。
DOI：
10.1083/jcb.200208092
发表时间：
2003-04-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hauf S;Cole RW;LaTerra S;Zimmer C;Schnapp G;Walter R;Heckel A;van Meel J;Rieder CL;Peters JM
通讯作者：
Peters JM