The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog.
The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog.
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DOI：
10.1016/j.ygyno.2011.04.034
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发表时间：
2011-08
影响因子：
4.7
通讯作者：
Siddik ZH
中科院分区：
文献类型：
--
作者：
He G;Kuang J;Khokhar AR;Siddik ZH
顺铂是一种损伤dna的抗肿瘤药物，对卵巢癌的治疗非常有效。它激活p53/p21通路的细胞毒性作用模式，但在G1期不诱导p21依赖性细胞周期阻滞。因此，我们研究了这一悖论，并使用模型模拟物DAP作为p21依赖性g1骤停的阳性对照。在精通p53的卵巢A2780肿瘤细胞中进行了研究，以检测顺铂或DAP与有丝分裂抑制剂诺可达唑联合使用后Cdk活性、细胞周期分布和DNA损伤信号。顺铂通过抑制Cdk2/cyclin A复合物在s期12小时持续诱导短暂的s期阻滞，然后通过抑制Cdc2/cyclin B复合物在12 - 18小时持续诱导G2/ m期阻滞。这些抑制作用与Chk1和Chk2的激活以及由此导致的Cdk2和Cdc2酪氨酸磷酸化的抑制增加有关。顺铂在约18小时内也能有效抑制g1期Cdk4/cyclin D1和Cdk2/cyclin E的活性。与此一致的是，将顺铂处理过的A2780、HCT-116p53−/−和HCT-116p21−/−肿瘤细胞暴露于nocodazole后显示，依赖于p53和p21的g1阻滞有限。相比之下，DAP的持久g1阻滞，未能激活Chk1和Chk2，不受诺可达唑的影响。顺铂诱导g1骤停，但水平较低。这主要是由于Cdk抑制首先在s期，然后在G2期，最后在G1期，有效地阻断了G2期的细胞，阻止了细胞在G1期的进展和阻滞。这些研究表明，顺铂明确激活g1 -检查点反应，但在S期和G2/ m期，Chk1/2激活和检查点反应降低了g1 -阻滞的保真度。
Cisplatin is a DNA-damaging antitumor agent that is highly effective in treating ovarian cancer. It activates the p53/p21 pathway for its cytotoxic mode of action, but it does not induce p21-dependent cell cycle arrest in G1. Therefore, we investigated this paradox, and used the model analog DAP as a positive control for p21-dependent G1-arrest. Studies were conducted in p53-proficient ovarian A2780 tumor cells to examine Cdk activity, cell cycle distribution and DNA damage signaling after cisplatin or DAP in combination with the mitotic inhibitor nocodazole. Cisplatin consistently induced transient S-phase arrest by inhibiting Cdk2/cyclin A complex in S-phase at 12 h and then a durable G2/M-arrest by inhibiting Cdc2/cyclin B complex at 12–18 h. These inhibitions were associated with Chk1 and Chk2 activation and resultant increase in inhibitory tyrosine phosphorylation of Cdk2 and Cdc2. Cisplatin also potently inhibited G1-phase Cdk4/cyclin D1 and Cdk2/cyclin E activities at ~18 h. In agreement, exposure of cisplatin-treated A2780, HCT-116p53−/− and HCT-116p21−/− tumor cells to nocodazole revealed limited G1-arrest that was dependent on p53 and p21. In contrast, the durable G1-arrest by DAP, which failed to activate Chk1 and Chk2, was unaffected by nocodazole. Cisplatin induced G1-arrest, but at an attenuated level. This was primarily due to orchestration of Cdk inhibition in S-phase first, then in G2, and finally in G1 that effectively blocked cells in G2 and prevented cells from progressing and arresting in G1. These studies demonstrate that cisplatin unequivocally activates G1-checkpoint response, but the fidelity of G1-arrest is compromised by Chk1/2 activation and checkpoint response in S- and G2/M-phase.
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通讯作者：
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作者：
He, GG;Siddik, ZH;Kuang, J
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