Withaferin a suppresses estrogen receptor-α expression in human breast cancer cells

Mol Carcinog. 2011 Aug;50(8):614-24. doi: 10.1002/mc.20760. Epub 2011 Mar 22.

Abstract

We have shown previously that withaferin A (WA), a promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits growth of MCF-7 and MDA-MB-231 human breast cancer cells in culture and MDA-MB-231 xenografts in vivo by causing apoptosis. However, the mechanism of WA-induced apoptosis is not fully understood. The present study was designed to systematically determine the role of tumor suppressor p53 and estrogen receptor-α (ER-α) in proapoptotic response to WA using MCF-7, T47D, and ER-α overexpressing MDA-MB-231 cells as a model. WA treatment resulted in induction as well as increased S15 phosphorylation of p53 in MCF-7 cells, but RNA interference of this tumor suppressor conferred modest protection at best against WA-induced apoptosis. WA-mediated growth inhibition and apoptosis induction in MCF-7 cells were significantly attenuated in the presence of 17β-estradiol (E2). Exposure of MCF-7 cells to WA resulted in a marked decrease in protein levels of ER-α (but not ER-β) and ER-α regulated gene product pS2, and this effect was markedly attenuated in the presence of E2. WA-mediated down-regulation of ER-α protein expression correlated with a decrease in its nuclear level, suppression of its mRNA level, and inhibition of E2-dependent activation of ERE2e1b-luciferase reporter gene. Ectopic expression of ER-α in the MDA-MB-231 cell line conferred partial but statistically significant protection against WA-mediated apoptosis, but not G2/M phase cell cycle arrest. Collectively, these results indicate that WA functions as an anti-estrogen, and the proapoptotic effect of this promising natural product is partially attenuated by p53 knockdown and E2-ER-α.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Down-Regulation / drug effects*
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism
  • Female
  • Humans
  • RNA, Messenger / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Up-Regulation
  • Withania / chemistry*
  • Withanolides / pharmacology*

Substances

  • Antineoplastic Agents, Phytogenic
  • Estrogen Receptor alpha
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • Withanolides
  • estrogen receptor alpha, human
  • withaferin A