摘要
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.
原文 | 英語 |
---|---|
頁(從 - 到) | 1776-1784 |
頁數 | 9 |
期刊 | International Journal of Cancer |
卷 | 119 |
發行號 | 8 |
DOIs | |
出版狀態 | 已發佈 - 10月 15 2006 |
對外發佈 | 是 |
ASJC Scopus subject areas
- 癌症研究
- 腫瘤科