Journal article
Withaferin A Suppresses Estrogen Receptor-alpha Expression in Human Breast Cancer Cells
Molecular carcinogenesis, Vol.50(8), pp.614-624
08/2011
DOI: 10.1002/mc.20760
PMCID: PMC3129407
PMID: 21432907
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-alpha (ER-alpha) in proapoptotic response to WA using MCF-7, T47D, and ER-alpha 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 17 beta-estradiol (E2). Exposure of MCF-7 cells to WA resulted in a marked decrease in protein levels of ER-alpha (but not ER-beta) and ER-alpha regulated gene product pS2, and this effect was markedly attenuated in the presence of E2. WA-mediated down-regulation of ER-alpha 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-alpha 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-alpha. (C) 2011 Wiley-Liss, Inc.
Details
- Title: Subtitle
- Withaferin A Suppresses Estrogen Receptor-alpha Expression in Human Breast Cancer Cells
- Creators
- Eun-Ryeong Hahm - UPMC Hillman Cancer CenterJoomin Lee - University of Pittsburgh School of MedicineYi Huang - University of Pittsburgh School of MedicineShivendra V. Singh - UPMC Hillman Cancer Center
- Resource Type
- Journal article
- Publication Details
- Molecular carcinogenesis, Vol.50(8), pp.614-624
- Publisher
- Wiley
- DOI
- 10.1002/mc.20760
- PMID
- 21432907
- PMCID
- PMC3129407
- ISSN
- 0899-1987
- eISSN
- 1098-2744
- Number of pages
- 11
- Grant note
- 1 RO1 CA142604-01 / USPHS by the National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01CA142604 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 08/2011
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383280502771
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