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

Shu Jun Chiu*, Jui-I Chao, Yi Jang Lee, Tzu Sheng Hsu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)63-70
Number of pages8
JournalToxicology Letters
Volume179
Issue number2
DOIs
StatePublished - 30 Jun 2008

Keywords

  • Apoptosis
  • Colorectal cancer cells
  • Oxaliplatin
  • Securin
  • p38 MAP kinase
  • γ-H2AX

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