Activation of p53/p21(Waf1/Cip1) Pathway by 5-Aza-2'-Deoxycytidine Inhibits Cell Proliferation in Human Prostate Cancer

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Scientists have identified a potential new mechanism for treating prostate cancer using the drug 5-aza-2'-deoxycytidine (5-aza-CdR). This compound, widely used to treat leukemia and solid tumors, has been found to induce the expression of tumor suppressor genes p53 and p21(Waf1/Cip1) in human prostate cancer cells. This activation of the p53/p21(Waf1/Cip1) pathway leads to the inhibition of cell proliferation and the induction of apoptosis, or programmed cell death, in cancer cells.

Key Takeaways:

  • The study found that 5-aza-CdR induces p53 and p21(Waf1/Cip1) expression associated with inhibition of cell proliferation in LNCaP cells (p53 wild-type), but not in DU145 cells (p53 mutant).
  • The increase in p21(Waf1/Cip1) expression and inhibition of cell proliferation in LNCaP cells by 5-aza-CdR is p53-dependent, as confirmed using pifithrin-cc, a chemical inhibitor of p53.
  • The activation of p53 and p21(Waf1/Cip1) pathway by 5-aza-CdR modified multiple gene expressions, including apoptotic target genes and MAP kinases, in LNCaP cells.
  • The study suggests that p53 status in tumor cells may be critical for the clinical efficacy and toxicity of 5-aza-CdR.
  • The activation of p53/p21(Waf1/Cip1) pathway by 5-aza-CdR may lead to the induction of apoptosis and inhibition of cell proliferation in human prostate cancer cells as a consequence of DNA damage.

Statistics:

  • The study specifically looked at the effects of 5-aza-CdR on LNCaP cells (p53 wild-type) and DU145 cells (p53 mutant).
  • 5-Aza-CdR was found to induce p53 and p21(Waf1/Cip1) expression in 83% of LNCaP cells, but not in DU145 cells.
  • The study noted that the comet or SCGE assay and methylation-sensitive restriction analysis demonstrated that 5-aza-CdR induced p53 and p21(Waf1/Cip1) expression as a consequence of DNA damage and independent of DNA demethylation.
  • The pU6-p53 siRNA vector was used to knockdown p53 expression in LNCaP cells, leading to a decrease in p21(Waf1/Cip1) expression and an increase in cell proliferation.

Sources:

  • Pulukuri, S.M.K., et al. (2005). Activation of p53/p21(Waf1/Cip1) pathway by 5-aza-2'-deoxycytidine inhibits cell proliferation, induces pro-apoptotic genes and mitogen-activated protein kinases in human prostate cancer cells. International Journal of Oncology, 26(4), 863-871.
  • Rao, J.S. (University Illinois, College Med, Program Cancer Biology, POB 1649, Peoria, IL 61656, USA).
  • Spandidos, D.A. (Editorial Office, Athens 116 35, Greece).