DNA mismatch repair as an effector for promoting phorbol ester-induced apoptotic DNA damage and cell killing: Implications in tumor promotion

Ching Tai Lin, Wei Hsin Lin, Kuan Der Lee, Pay Yu Tzeng

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Phorbol ester was known to activate protein kinase C (PKC) and exert numerous cellular effects, including proliferation, apoptosis, and oncogenic transformation. How phorbol ester stimulates both apoptosis and tumor promotion is not clear. Here DNA mismatch repair (MMR)-proficient human colon cancer cells (DLD-1+Ch2; hMSH6+) treated with l2-O-tetradecanoylphorbol-13- acetate (TPA) undergo rapid cell death, which is significantly abolished by staurosporine (PKC inhibitor) or antioxidant, compared with the paired MMR-deficient (DLD-1; hMSH6-) cells. Induction of reactive oxygen species (ROS) by TPA is shown to be one of downstream effectors required, but not sufficient, for cell killing as it is also observed in DLD-1 cells. Strikingly, DLD-1+Ch2 cells selected for resistance to TPA are found to lose the expression of hMSH6. Treatment of TPA-resistant DLD4+Ch2 cells with 5-aza-2′-deoxycytidine, not only restores hMSH6 expression but also resensitizes TPA-resistant cells to TPA, suggesting that expression of hMSH6 is transcriptionally silenced by cytosine methylation confirmed directly by bisulfite sequencing. Knockdown hMSH6 or hPMS2 with siRNA in DLD-1+Ch2 cells resulted in more resistant to TPA-induced cell killing, further suggesting that MMR proteins involve in TPA or ROS-induced cell killing. Results suggest that deficiency in MMR could promote tumorigenesis by inhibiting apoptotic responses to ROS-mediated DNA damages as ROS are continuously produced as a byproduct of normal metabolism.

Original languageEnglish
Pages (from-to)1776-1784
Number of pages9
JournalInternational Journal of Cancer
Volume119
Issue number8
DOIs
Publication statusPublished - Oct 15 2006
Externally publishedYes

    Fingerprint

Keywords

  • DNA methylation
  • DNA mismatch repair
  • Drug resistance
  • Gene silencing
  • Phorbol ester

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this