Hahm, ER and Moura, MB and Kelley, EE and van Houten, B and Shiva, S and Singh, SV
(2011)
Withaferin a-induced apoptosis in human breast cancer cells is mediated by reactive oxygen species.
PLoS ONE, 6 (8).
Abstract
Withaferin A (WA), a promising anticancer constituent of Ayurvedic medicinal plant Withania somnifera, inhibits growth of MDA-MB-231 and MCF-7 human breast cancer cells in culture and MDA-MB-231 xenografts in vivo in association with apoptosis induction, but the mechanism of cell death is not fully understood. We now demonstrate, for the first time, that WA-induced apoptosis is mediated by reactive oxygen species (ROS) production due to inhibition of mitochondrial respiration. WA treatment caused ROS production in MDA-MB-231 and MCF-7 cells, but not in a normal human mammary epithelial cell line (HMEC). The HMEC was also resistant to WA-induced apoptosis. WA-mediated ROS production as well as apoptotic histone-associated DNA fragment release into the cytosol was significantly attenuated by ectopic expression of Cu,Zn-superoxide dismutase in both MDA-MB-231 and MCF-7 cells. ROS production resulting from WA exposure was accompanied by inhibition of oxidative phosphorylation and inhibition of complex III activity. Mitochondrial DNA-deficient Rho-0 variants of MDA-MB-231 and MCF-7 cells were resistant to WA-induced ROS production, collapse of mitochondrial membrane potential, and apoptosis compared with respective wild-type cells. WA treatment resulted in activation of Bax and Bak in MDA-MB-231 and MCF-7 cells, and SV40 immortalized embryonic fibroblasts derived from Bax and Bak double knockout mouse were significantly more resistant to WA-induced apoptosis compared with fibroblasts derived from wild-type mouse. In conclusion, the present study provides novel insight into the molecular circuitry of WA-induced apoptosis involving ROS production and activation of Bax/Bak. © 2011 Hahm et al.
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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
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Contributors: |
Contribution | Contributors Name | Email | Pitt Username | ORCID |
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Editor | Chandra, Dhyan | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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Centers: |
Other Centers, Institutes, Offices, or Units > Pittsburgh Cancer Institute |
Date: |
15 August 2011 |
Date Type: |
Publication |
Journal or Publication Title: |
PLoS ONE |
Volume: |
6 |
Number: |
8 |
DOI or Unique Handle: |
10.1371/journal.pone.0023354 |
Schools and Programs: |
School of Medicine > Anesthesiology School of Medicine > Pharmacology and Chemical Biology |
Refereed: |
Yes |
MeSH Headings: |
Adenosine Triphosphate--metabolism; Animals; Apoptosis--drug effects; Breast Neoplasms--enzymology; Breast Neoplasms--pathology; Cell Line, Tumor; Drug Resistance, Neoplasm--drug effects; Drug Screening Assays, Antitumor; Electron Transport Complex III--metabolism; Female; Humans; Mice; Oxidative Phosphorylation--drug effects; Protective Agents--pharmacology; Reactive Oxygen Species--metabolism; Superoxide Dismutase--metabolism; Withanolides--chemistry; Withanolides--pharmacology; bcl-2 Homologous Antagonist-Killer Protein--metabolism; bcl-2-Associated X Protein--metabolism; rho GTP-Binding Proteins--metabolism |
Other ID: |
NLM PMC3154436 |
PubMed Central ID: |
PMC3154436 |
PubMed ID: |
21853114 |
Date Deposited: |
05 Sep 2012 18:51 |
Last Modified: |
02 Feb 2019 21:55 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/13885 |
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