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首页> 外文期刊>Apoptosis >Shogaols at proapoptotic concentrations induce G2/M arrest and aberrant mitotic cell death associated with tubulin aggregation
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Shogaols at proapoptotic concentrations induce G2/M arrest and aberrant mitotic cell death associated with tubulin aggregation

机译：促凋亡的Shogaols诱导与微管蛋白聚集相关的G 2 / M阻滞和有丝分裂细胞异常死亡

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Shogaols have been previously reported to induce cancer cell death via multiple mechanisms, among which one analog 6-shogaol has been reported to cause microtubule damage through specific reaction with sulfhydryl groups in tubulin. In this study, a series of shogaols with different side chain lengths (4-, 6-, 8- and 10-shogaol) was synthesized and evaluated for antiproliferative activity in HCT 116 colon carcinoma and SH-SY5Y neuroblastoma cells. 4- and 6-shogaol were identified as lead compounds possessing the strongest antiproliferative activity. In the soft agar assay, the lead shogaols displayed dose-dependent inhibition on cancer cell colony formation under anchorage-independent conditions. Using HCT 116 as the selected cancer cell line, the molecular events linking shogaols-induced G2/M cell cycle arrest to apoptosis characterized by caspase 3 and PARP cleavage were investigated. At sublethal concentrations, the halt at G2/M phase was alleviated along time and cells survived. Conversely, proapoptotic concentrations of 4- and 6-shogaol induced irreversible G2/M arrest that was at least in part associated with down-regulation of cell cycle checkpoint proteins cdk1, cyclin B and cdc25C, as well as spindle assembly checkpoint proteins mad2, cdc20 and survivin. A dose- and time-dependent accumulation of insoluble tubulin in the insoluble fractions of cell lysates provided evidence that G2 checkpoint failure led to disruption of microtubule turnover. In summary, our results conclude that shogaols cause apoptosis by inducing aberrant mitosis at least through the attenuation of cell cycle and spindle assembly checkpoint proteins.
机译：以前曾报道过Shogaols通过多种机制诱导癌细胞死亡，其中一种类似物6-shogaol已通过与微管蛋白中的巯基发生特异性反应而引起微管损伤。在这项研究中，合成了一系列具有不同侧链长度（4-，6-，8和10-shogaol）的shogaol，并评估了它们在HCT 116结肠癌和SH-SY5Y神经母细胞瘤细胞中的抗增殖活性。已鉴定出4-和6-shogaol是具有最强的抗增殖活性的先导化合物。在软琼脂分析中，无铅铅酚对锚定非依赖性条件下的癌细胞集落形成具有剂量依赖性抑制作用。以HCT 116为选择的癌细胞系，研究了由shogaols诱导的G 2 / M细胞周期阻滞与以胱天蛋白酶3和PARP裂解为特征的凋亡相关的分子事件。在亚致死浓度下，随着时间的推移，G 2 / M期的停滞得到缓解，细胞得以存活。相反，促凋亡浓度的4和6-shogaol诱导的不可逆的G 2 / M停滞至少部分与细胞周期检查点蛋白cdk1，cyclin B和cdc25C的下调有关作为纺锤体装配检查点蛋白mad2，cdc20和survivin。细胞溶解产物的不溶级分中不溶性微管蛋白的剂量依赖性和时间依赖性积累提供了证据，表明G 2 检查点失效导致微管更新的破坏。总而言之，我们的研究结果得出结论，shogaols至少通过减弱细胞周期和纺锤体装配检查点蛋白来诱导异常的有丝分裂，从而导致细胞凋亡。

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