Down-Regulation of Inhibitor of Apoptosis Proteins by Deguelin Selectively Induces Apoptosis in Breast Cancer Cells

• Authors: Xianghong Peng, Emory University; Prasanthi Karna, Emory University; Ruth M. O'Regan, Emory University; XiuJu Liu, Emory University; Rajesh Naithani, University of Illinois at Chicago; Robert M. Moriarty, University of Illinois at Chicago; William C Wood, Emory University; Ho-Young Lee, University of Texas; Lily Yang, Emory University
• Journal Title: Molecular Pharmacology
• Volume: Volume 71, Number 1
• Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET) | 2007-01, Pages 101-111
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1124/mol.106.027367
• Subjects: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

The identification of differentially regulated apoptotic signals in normal and tumor cells allows the development of cancer cell-selective therapies. Increasing evidence shows that the inhibitor of apoptosis (IAP) proteins survivin and XIAP are highly expressed in tumor cells but are absent or have very low levels of expression in normal adult tissues. We found that inhibiting AKT activity with 10 to 100 nM deguelin, a small molecule derived from natural products, markedly reduced the levels of both survivin and XIAP, inducing apoptosis in human breast cancer cells but not in normal cells. It is noteworthy that we detected an elevated level of cleaved poly(ADP-ribose) polymerase, a signature of caspase activation, without a significant increase in caspase activity in deguelin-treated cancer cells. Our results suggest that severe down-regulation of the IAPs by deguelin releases their inhibitory activity over pre-existing active caspases present in cancer cells, inducing apoptosis without the need for further caspase activation. Because normal cells have very low levels of p-AKT, XIAP, survivin, and preexisting caspase activity, deguelin had little effect on those cells. In addition, we found that combining deguelin with chemotherapy drugs enhanced drug-induced apoptosis selectively in human tumor cells, which suggests that deguelin has great potential for chemosensitization and could represent a new therapeutic agent for treatment of breast cancer.