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首页> 外文期刊>Cell cycle >GSI promotes vincristine-induced apoptosis by enhancing multi-polar spindle formation
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GSI promotes vincristine-induced apoptosis by enhancing multi-polar spindle formation

机译:GSI通过增强多极纺锤体形成促进长春新碱诱导的细胞凋亡

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Gamma secretase inhibitors (GSI), cell-permeable small-molecule inhibitors of gamma secretase activity, had been originally developed for the treatment of Alzheimer disease. In recent years, it has been exploited in cancer research to inhibit Notch signaling that is aberrantly activated in various cancers. We previously found that GSI could synergize with anti-microtubule agent, vincristine (VCR) in a Notch-independent manner. Here, we delineate the underlying cell cycle-related mechanism using HeLa cells, which have strong mitotic checkpoints. GSI enhanced VCR-induced cell death, although GSI alone did not affect cell viability at all. GSI augmented VCR-induced mitotic arrest in a dose-dependent manner, which was preceded by apoptotic cell death, as shown by an increase in Annexin V-positive and caspase-positive cell population. Furthermore, GSI amplified multi-polar spindle formation triggered by VCR. Altogether, we show the evidence that GSI enhances VCR-induced apoptosis in HeLa cells via multi-polar mitotic spindle formation, independent of Notch signaling. These data suggest that one or more GS substrates, yet to be identified, in a post-GS processed form, may play a role in maintaining functional centrosomes/mitotic spindles. More significantly, the synergistic effect of GSI in combination with VCR could be exploited in clinical setting to improve the efficacy of VCR.
机译:γ分泌酶抑制剂(GSI)是γ分泌酶活性的细胞可渗透性小分子,最初开发用于治疗阿尔茨海默氏病。近年来,已经在癌症研究中利用它来抑制在各种癌症中异常激活的Notch信号传导。我们以前发现,GSI可以与Notch无关的方式与抗微管药长春新碱(VCR)协同作用。在这里,我们描述了使用具有强大的有丝分裂检查点的HeLa细胞与细胞周期相关的潜在机制。 GSI增强了VCR诱导的细胞死亡,尽管仅GSI根本不影响细胞活力。 GSI以剂量依赖的方式增强了VCR诱导的有丝分裂阻滞,在此之前凋亡细胞死亡,如Annexin V阳性和caspase阳性细胞数量的增加所表明。此外,GSI放大了VCR触发的多极主轴形成。总而言之,我们显示了证据,即GSI通过多极有丝分裂纺锤体形成增强了VCR诱导的HeLa细胞凋亡,而与Notch信号无关。这些数据表明,尚待鉴定的一种或多种GS底物(以GS后加工的形式)可能在维持功能性中心体/有丝分裂纺锤体中起作用。更重要的是,在临床环境中可以利用GSI与VCR的协同作用来提高VCR的疗效。

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