Antiproliferative Fate of the Tetraploid Formed after Mitotic Slippage and Its Promotion; A Novel Target for Cancer Therapy Based on Microtubule Poisons.
Antiproliferative Fate of the Tetraploid Formed after Mitotic Slippage and Its Promotion; A Novel Target for Cancer Therapy Based on Microtubule Poisons.
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DOI：
10.3390/molecules21050663
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发表时间：
2016-05-19
期刊：
影响因子：
--
通讯作者：
Inoue T
中科院分区：
文献类型：
--
作者：
Nakayama Y;Inoue T
微管毒素抑制纺锤体功能，导致纺锤体组装检查点（SAC）的激活和有丝分裂停止。细胞死亡发生在延长有丝分裂是微管毒素在癌症治疗的首要目标。然而，即使存在微管毒物，SAC和有丝分裂阻滞也不是永久性的，存活的细胞在没有细胞分裂（有丝分裂滑脱）的情况下退出有丝分裂，成为四倍体。基于微管毒素的癌症治疗的另一个目标是有丝分裂滑脱后的抗增殖命运。这两种基于微管毒物的癌症治疗的最终目标都涉及一种被定义为有丝分裂灾难的机制的诱导，这是一种真正的内在肿瘤抑制机制，它感知有丝分裂失败，并通过驱动细胞进入不可逆转的抗增殖死亡或衰老的命运来做出反应。有丝分裂滑脱后抗增殖命运的机制尚不清楚。我们提供有丝分裂灾难的概述，并解释新的见解强调基础自噬水平和有丝分裂滑移后抗增殖命运之间的因果关系，并提出可能的改进策略。此外，我们还讨论了有丝分裂滑移后核突变（微核、多核）的特征，以及一种可能的新型核变化（聚类微核）。
Microtubule poisons inhibit spindle function, leading to activation of spindle assembly checkpoint (SAC) and mitotic arrest. Cell death occurring in prolonged mitosis is the first target of microtubule poisons in cancer therapies. However, even in the presence of microtubule poisons, SAC and mitotic arrest are not permanent, and the surviving cells exit the mitosis without cytokinesis (mitotic slippage), becoming tetraploid. Another target of microtubule poisons-based cancer therapy is antiproliferative fate after mitotic slippage. The ultimate goal of both the microtubule poisons-based cancer therapies involves the induction of a mechanism defined as mitotic catastrophe, which is a bona fide intrinsic oncosuppressive mechanism that senses mitotic failure and responds by driving a cell to an irreversible antiproliferative fate of death or senescence. This mechanism of antiproliferative fate after mitotic slippage is not as well understood. We provide an overview of mitotic catastrophe, and explain new insights underscoring a causal association between basal autophagy levels and antiproliferative fate after mitotic slippage, and propose possible improved strategies. Additionally, we discuss nuclear alterations characterizing the mitotic catastrophe (micronuclei, multinuclei) after mitotic slippage, and a possible new type of nuclear alteration (clustered micronuclei).
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