Autophagy Fails to Alter Withaferin A-Mediated Lethality in Human Breast Cancer Cells

Title:Autophagy Fails to Alter Withaferin A-Mediated Lethality in Human Breast Cancer Cells

Volume: 13 Issue: 6

Author(s): Eun-Ryeong Hahm and Shivendra V. Singh

Affiliation:

Keywords: Autophagy, Atg5, Beclin1, breast cancer, MCF-7, MDA-MB-231, withaferin A.

Abstract: We have shown previously that withaferin A (WA), which is a highly promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits viability of cultured breast cancer cells in association with reactive oxygen species (ROS)-dependent apoptosis induction. Because ROS production is implicated in induction of autophagy, which is an evolutionary conserved process for bulk degradation of cellular components including organelles (e.g., mitochondria) and considered a valid cancer chemotherapeutic target, we questioned whether WA treatment resulted in autophagy induction. Indeed exposure of MDA-MB-231 and MCF-7 human breast cancer cells as well as a spontaneously immortalized and non-tumorigenic normal human mammary epithelial cell line (MCF-10A) to pharmacologic concentration of WA resulted in autophagy as evidenced by transmission electron microscopy, processing of microtubuleassociated protein 1 light chain 3 isoform B, and/or acridine orange staining. Inhibition of MDA-MB-231 xenograft growth in vivo by WA administration was also associated with a significant increase in level of LC3 protein in the tumor. However, WA-mediated inhibition of MDA-MB-231 and MCF-7 cell viability was not compromised either by pharmacological suppression of autophagy using 3-methyl adenine or genetic repression of autophagy by RNA interference of Atg5, a critical component of the autophagic machinery. Finally, Beclin1 was dispensable for WA-mediated autophagy as well as inhibition of MDA-MB-231 cell viability. Based on these observations we conclude that autophagy induction fails to have any meaningful impact on WA-mediated lethality in breast cancer cells, which may be a therapeutic advantage because autophagy serves to protect against apoptosis by several anticancer agents.

Cite this article as:

Hahm Eun-Ryeong and Singh V. Shivendra, Autophagy Fails to Alter Withaferin A-Mediated Lethality in Human Breast Cancer Cells, Current Cancer Drug Targets 2013; 13 (6) . https://dx.doi.org/10.2174/15680096113139990039