Activation of the p53 DNA Damage Response Pathway after Inhibition of DNA Methyltransferase by 5-Aza-2′-deoxycytidine (original) (raw)
Research ArticleArticle
Molecular Pharmacology April 2001, 59 (4) 751-757; DOI: https://doi.org/10.1124/mol.59.4.751
Abstract
Transcriptional silencing of tumor suppressor genes by DNA methylation occurs in cancer cell lines and in human tumors. This has led to the pursuit of DNA methyltransferase inhibition as a drug target. 5-Aza-2′-deoxycytidine [5-aza-CdR (decitabine)], a potent inhibitor of DNA methyltransferase, is a drug currently in clinical trials for the treatment of solid tumors and leukemia. The efficacy of 5-aza-CdR may be related to the induction of methylation-silenced tumor suppressor genes, genomic hypomethylation, and/or enzyme-DNA adduct formation. Here, we test the hypothesis that 5-aza-CdR treatment is perceived as DNA damage, as assessed by the activation of the tumor suppressor p53. We show that 1) colon tumor cell lines expressing wild-type p53 are more sensitive to 5-aza-CdR mediated growth arrest and cytotoxicity; 2) the response to 5-aza-CdR treatment includes the induction and activation of wild-type but not mutant p53 protein; and 3) the induction of the downstream p53 target gene p21 is partially p53-dependent. The induction of p53 protein after 5-aza-CdR treatment did not correlate with an increase in p53 transcripts, indicating that hypomethylation at the p53 promoter does not account for the p53 response. It is relevant that 5-aza-CdR has shown the greatest promise in clinical trials for the treatment of chronic myelogenous leukemia, a malignancy in which functional p53 is often retained. Our data raise the hypothesis that p53 activation may contribute to the clinical efficacy and/or toxicity of 5-aza-CdR.
Footnotes
Received November 2, 2000.
Accepted January 3, 2001.
Send reprint requests to: Dr. David A. Jones, Division of Molecular Pharmacology, Huntsman Cancer Institute, 2000 Circle of Hope, University of Utah, Salt Lake City, UT 84112. E-mail:david.jones{at}hci.utah.edu
This work was supported by a Postdoctoral Fellowship PF-99–151-01-CDD from the American Cancer Society (to A.R.K.) and by National Institutes of Health P01-CA73992 (to D.A.J.).
This work was previously presented under the title “Impact of p53 status on the response of tumor cells to 5-aza-2′-deoxycytide treatment” at the American Association of Cancer Research Annual Meeting, San Francisco, CA, 1–5 April, 2000.
The American Society for Pharmacology and Experimental Therapeutics
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