Diallyl trisulfide-induced apoptosis in human cancer cells is linked to checkpoint kinase 1-mediated mitotic arrest.
Diallyl trisulfide-induced apoptosis in human cancer cells is linked to checkpoint kinase 1-mediated mitotic arrest.
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DOI：
10.1002/mc.20553
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发表时间：
2009-11
影响因子：
4.6
通讯作者：
Singh, Shivendra V.
中科院分区：
文献类型：
--
作者：
Xiao, Dong;Zeng, Yan;Singh, Shivendra V.
大蒜的化学防癌成分二烯丙基三硫化物(DATS)对培养的人癌细胞的生长抑制作用与Chk1(Chk1)介导的有丝分裂停滞有关，但停滞在有丝分裂中的细胞的命运仍不明朗。以LNCaP和HCT-116人癌细胞为模型，我们现在证明了DATS暴露导致Chk1介导的有丝分裂停滞导致细胞凋亡。DATS作用后，LNCaP和HCT-116细胞均出现G2期停滞和有丝分裂停滞。伴随着细胞周期蛋白依赖性激酶1(CDK1)、细胞分裂周期(CDC)25B和CDC25C的下调，导致CDK1酪氨酸磷酸化(失活)。DATS介导的有丝分裂停滞与后期促进复合体/环体的失活有关，其底物cyClinB1和securin的积累证明了这一点。DATS处理增加了Chk1(Ser317)的激活磷酸化，瞬时转染靶向Chk1的siRNA对DATS诱导的两种细胞的有丝分裂停止都有明显的保护作用。在LNCaP和HCT-116细胞中，Chk1蛋白的敲除也提供了部分但在统计学上显著的保护作用，防止DATS暴露引起的DNA凋亡和caspase-3的激活。尽管DATS处理导致了P53的稳定和Ser15磷酸化，但P53蛋白的下调并不能挽救DATS诱导的有丝分裂停止。总之，本研究的结果表明，DATS诱导的人类癌细胞有丝分裂停止的Chk1依赖性不受P53状态的影响，并且在DATS作用下被阻止在有丝分裂中的细胞被驱动成凋亡性DNA片段化。
Growth suppressive effect of diallyl trisulfide (DATS), a promising cancer chemopreventive constituent of garlic, against cultured human cancer cells correlates with checkpoint kinase 1 (Chk1)-mediated mitotic arrest, but the fate of the cells arrested in mitosis remains elusive. Using LNCaP and HCT-116 human cancer cells as a model, we now demonstrate that the Chk1-mediated mitotic arrest resulting from DATS exposure leads to apoptosis. The DATS exposure resulted in G2 phase and mitotic arrest in both LNCaP and HCT-116 cell lines. The G2 arrest was accompanied by down-regulation of cyclin-dependent kinase 1 (Cdk1), cell division cycle (Cdc) 25B, and Cdc25C leading to Tyr15 phosphorylation of Cdk1 (inactivation). The DATS-mediated mitotic arrest correlated with inactivation of anaphase-promoting complex/cyclosome as evidenced by accumulation of its substrates cyclinB1 and securin. The DATS treatment increased activating phosphorylation of Chk1 (Ser317) and transient transfection with Chk1-targeted siRNA conferred significant protection against DATS-induced mitotic arrest in both cell lines. The Chk1 protein knockdown also afforded partial yet statistically significant protection against apoptotic DNA fragmentation and caspase-3 activation resulting from DATS exposure in both LNCaP and HCT-116 cells. Even though DATS treatment resulted in stabilization and Ser15 phosphorylation of p53, the knockdown of p53 protein failed to rescue DATS-induced mitotic arrest. In conclusion, the results of the present study indicate that Chk1-dependence of DATS-induced mitotic arrest in human cancer cells is not influenced by the p53 status and cells arrested in mitosis upon DATS exposure are driven to apoptotic DNA fragmentation.
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影响因子：
11.2
作者：
Antosiewicz, Jedrzej;Herman-Antosiewicz, Anna;Singh, Shivendra V.
通讯作者：
Singh, Shivendra V.
影响因子：
4.1
作者：
BRADY, JF;ISHIZAKI, H;YANG, CS
通讯作者：
YANG, CS
影响因子：
4.8
作者：
Bembenek, J;Yu, HT
通讯作者：
Yu, HT
DOI：
10.1111/j.1349-7006.1999.tb00791.x
发表时间：
1999-06
期刊：
Japanese journal of cancer research : Gann
影响因子：
--
作者：
Gao CM;Takezaki T;Ding JH;Li MS;Tajima K
通讯作者：
Tajima K
影响因子：
3.9
作者：
Hu, X;Benson, PJ;Singh, SV
通讯作者：
Singh, SV