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

Toxicol Lett. 2008 Jun 30;179(2):63-70. doi: 10.1016/j.toxlet.2008.04.004. Epub 2008 May 21.


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 microM 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Caspase Inhibitors
  • Colorectal Neoplasms
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • HCT116 Cells
  • Histones / biosynthesis*
  • Histones / genetics
  • Humans
  • Imidazoles / pharmacology
  • Microscopy, Confocal
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis*
  • Organoplatinum Compounds / pharmacology*
  • Phosphorylation
  • Pyridines / pharmacology*
  • RNA, Small Interfering / pharmacology
  • Securin
  • Time Factors
  • Transfection
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Antineoplastic Agents
  • Caspase Inhibitors
  • Enzyme Inhibitors
  • H2AX protein, human
  • Histones
  • Imidazoles
  • Neoplasm Proteins
  • Organoplatinum Compounds
  • Pyridines
  • RNA, Small Interfering
  • Securin
  • oxiplatin
  • pituitary tumor-transforming protein 1, human
  • p38 Mitogen-Activated Protein Kinases
  • 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole