Involvement of Chk1-Cdc25A-cyclin A/CDk2 pathway in simvastatin induced S-phase cell cycle arrest and apoptosis in multiple myeloma cells
Involvement of Chk1-Cdc25A-cyclin A/CDk2 pathway in simvastatin induced S-phase cell cycle arrest and apoptosis in multiple myeloma cells
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Chk1-Cdc25A-cyclin A/CDk2 通路参与辛伐他汀诱导多发性骨髓瘤细胞 S 期细胞周期阻滞和凋亡
DOI：
10.1016/j.ejphar.2011.09.031
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发表时间：
2011-11-30
影响因子：
5
通讯作者：
Guan, Yong-Yuan
中科院分区：
文献类型：
--
作者：
Tu, Yong-Sheng;Kang, Xiao-Long;Guan, Yong-Yuan
他汀类药物通过抑制香叶基香叶基化而有效地抑制肿瘤细胞增殖并诱导其凋亡，但其新的分子机制尚不清楚。最近发现辛伐他汀与Chk1抑制剂7-hydroxystaurosporine（UCN-01）协同诱导骨髓瘤细胞凋亡。因此，我们假设Chk 1在辛伐他汀的抗骨髓瘤作用中起作用。有趣的是，我们发现辛伐他汀引起S期细胞周期的剂量依赖性增加，并诱导显着的凋亡。Western blot结果显示辛伐他汀诱导的S期细胞周期阻滞与Chk 1的激活、Cdc25A、cyclin A和CDK 2的表达下调有关。此外，辛伐他汀诱导的细胞凋亡伴随着Bcl-2蛋白表达减少，细胞溶质细胞色素c水平增加，caspase 9和caspase 3的激活。进一步的研究表明，通过Chk1特异性siRNA沉默Chk1表达抑制辛伐他汀诱导的Chk1活化，下调Cdc25A，cyclin A和CDK2表达，并减少S期细胞周期阻滞。此外，抑制Chk1表达增强辛伐他汀诱导的Bcl-2下调，caspase 9裂解和随后的细胞凋亡。这些结果表明，Chk1-Cdc25A-cyclin A/CDk2通路参与了辛伐他汀诱导的多发性骨髓瘤细胞S期细胞周期阻滞和凋亡。(C)2011 Elsevier B.V.保留所有权利。
Statins have been demonstrated to effectively inhibit proliferation and induce apoptosis in cancer cells by inhibition of geranylgeranylation, however its novel molecular mechanism remains to be determined. Recently simvastatin has been found to result in the synergistic induction of apoptosis with 7-hydroxystaurosporine (UCN-01) (a Chk1 inhibitor) in myeloma cells. Therefore we hypothesized that Chk1 plays a role in the anti-myeloma effect of simvastatin. Interestingly, we found that simvastatin caused a dose-dependent increase in S phase cell cycle and induced significant apoptosis. The results of western blot showed that simvastatin-induced S-phase cell cycle arrest was associated with activation of Chk1, downregulation of Cdc25A, cyclin A and CDK2 expression. Additionally, simvastatin-induced apoptosis was accompanied by diminished Bcl-2 protein expression, increased cytosolic cytochrome c level, and activation of caspase 9 and caspase 3. Further investigation revealed that silence of Chk1 expression by Chk1 specific siRNA inhibited simvastatin-induced activation of Chk1, downregulation of Cdc25A, cyclin A and CDK2 expression, and diminished S phase cell cycle arrest. Additionally, inhibition of Chk1 expression enhanced simvastatin-induced downregulation of Bcl-2, caspase 9 cleavage and subsequent apoptosis. These results suggested that the Chk1-Cdc25A-cyclin A/CDk2 pathway was involved in simvastatin-induced S-phase cell cycle arrest and apoptosis in multiple myeloma cell lines. (C) 2011 Elsevier B.V. All rights reserved.