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DNA mismatch repair as an effector for promoting phorbol ester‐induced apoptotic DNA damage and cell killing: Implications in tumor promotion
Author(s) -
Lin ChingTai,
Lin WeiHsin,
Lee KuanDer,
Tzeng PayYu
Publication year - 2006
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22068
Subject(s) - dna damage , apoptosis , carcinogenesis , programmed cell death , reactive oxygen species , dna repair , staurosporine , biology , cancer research , microbiology and biotechnology , tumor promotion , protein kinase c , dna , signal transduction , biochemistry , cancer , genetics
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 12‐ 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 DLD‐1+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. © 2006 Wiley‐Liss, Inc.