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
- 作者：Shu-Jun Chiu ; Jui-I Chao ; Yi-Jang Lee ; Tzu-Sheng Hsu
- 关键词：γ ; -H2AX ; Securin ; Apoptosis ; p38 MAP kinase ; Oxaliplatin ; Colorectal cancer cells
- 刊名：Toxicology Letters
- 出版年：2008
- 期刊代码：49_03784274
- 类别：pha
- 出版时间：30 June 2008
- 卷：179
- 期：2
- 页码：63-70
- 文件大小：1059 K
摘要
Oxaliplatin, a chemotherapeutic drug, induces DNA strand breaks leading to apoptosis in colorectal cancer cells. γ-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 γ-H2AX and securin on the oxaliplatin-induced apoptosis in human colorectal cancer cells remain unclear. Treatment of oxaliplatin (1–10 μM for 6–24 h) persistently induced γ-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 γ-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 γ-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 γ-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 γ-H2AX formation in the oxaliplatin-induced apoptosis of human colorectal cancer cells.