Regulation of gamma-H2AX and securin contribute to apoptosis by oxaliplatin via a p38 mitogen-activated protein kinase-dependent pathway in human colorectal cancer cells
Regulation of gamma-H2AX and securin contribute to apoptosis by oxaliplatin via a p38 mitogen-activated protein kinase-dependent pathway in human colorectal cancer cells
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DOI：
10.1016/j.toxlet.2008.04.004
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发表时间：
2008-06-30
影响因子：
3.5
通讯作者：
Hsu, Tzu-Sheng
中科院分区：
文献类型：
--
作者：
Chiu, Shu-Jun;Chao, Jui-I;Hsu, Tzu-Sheng
奥沙利铂是一种化疗药物，可诱导DNA链断裂导致结直肠癌细胞凋亡。γ -H2AX是一种磷酸化组蛋白H2AX，可以作为DNA双链断裂（dsb）的标记物。研究表明，安全蛋白在多种癌细胞中过度表达。然而，γ - h2ax和securin在奥沙利铂诱导的人结直肠癌细胞凋亡中的作用尚不清楚。奥沙利铂（1-10 μ M, 6-24h）持续诱导γ - h2ax形成，并以时间和浓度依赖的方式抑制HCT116野生型结直肠癌细胞中securin蛋白的表达。与HCT116 securin野生型细胞相比，奥沙利铂对HCT116无securin的结直肠癌细胞凋亡和持久性γ - h2ax形成的诱导作用减弱。此外，在暴露于奥沙利铂的细胞中，特定的caspase抑制剂阻断caspase降低了γ - h2ax蛋白的水平和细胞毒性，但增加了securin蛋白的表达。转染H2AX短干扰RNA敲低H2AX基因可增强奥沙利铂诱导的细胞死亡。有趣的是，奥沙利铂显著增加了p38丝裂原活化蛋白激酶（MAPK）的磷酸化。在奥沙利铂处理的细胞中，预处理特异性p38 MAPK抑制剂SB202190可降低γ - h2ax蛋白并增加securin蛋白的表达。我们的研究结果表明，p38 MAPK可能在奥沙利铂诱导的人结直肠癌细胞凋亡中反向调节securin蛋白的表达和γ - h2ax的形成。2008爱思唯尔爱尔兰有限公司版权所有。
Oxaliplatin, a chemotherapeutic drug, induces DNA strand breaks leading to apoptosis in colorectal cancer cells. gamma-H2AX is a phosphorylated histone H2AX that can act as a marker of DNA double-strand breaks (DSBs). It has been shown that securin proteins were over-expressed in a variety of cancer cells. However, the roles of gamma-H2AX and securin on the oxaliplatin-induced apoptosis in human colorectal cancer cells remain unclear. Treatment of oxaliplatin (1-10 mu M for 6-24h) persistently induced gamma-H2AX formation and inhibited securin protein expression via a time- and concentration-dependent manner in HCT116 securin-wild type colorectal cancer cells. Compared with HCT116 securin-wild type cells, the induction of apoptosis and persistent gamma-H2AX formation by oxaliplatin was reduced in the HCT116 securin-null colorectal cancer cells. Furthermore, the blockage of caspases by specific caspase inhibitors reduced the levels of gamma-H2AX proteins and cytotoxicity but increased securin protein expression in the oxaliplatin-exposed cells. The gene knockdown of H2AX by transfection with a short interfering RNA of H2AX enhanced the oxaliplatin-induced cell death. Interestingly, the phosphorylation of p38 mitogen-activated protein kinase (MAPK) was markedly increased by oxaliplatin. Pre-treatment of a specific p38 MAPK inhibitor SB202190 reduced gamma-H2AX proteins and increased securin protein expression in the oxaliplatin-treated cells. Our findings suggest that p38 MAPK may oppositely regulate securin protein expression and gamma-H2AX formation in the oxaliplatin-induced apoptosis of human colorectal cancer cells. (C) 2008 Elsevier Ireland Ltd. All rights reserved.