Beta-arrestin 2 modulates resveratrol-induced apoptosis and regulation of Akt/GSK3β pathways

Background: Resveratrol is emerging as a novel anticancer agent. However, the mechanism(s) by which resveratrol exerts its effects on endometrial cancer (EC) are unknown. We previously reported that beta-arrestin 2 plays a critical role in cell apoptosis. The role of beta-arrestin 2 in resveratrol modulation of endometrial cancer cell apoptosis remains to be established. Scope of Review: EC cells HEC1B and Ishikawa were transfected with either beta-arrestin 2 RNA interfering (RNAi) plasmid or beta-arrestin 2 full-length plasmid and control vector. The cells were then exposed to differing concentrations of resveratrol. Apoptotic cells were detected by TUNEL assay. Expression of total and phosphorylated Akt (p-Akt), total and phosphorylated glycogen synthase kinase 3 beta (p-GSK3 beta), and caspase-3 were determined by Western blot analysis. Our data demonstrate that inhibition of beta-arrestin 2 increases the number of apoptotic cells and caspase-3 activation. Additionally beta-arrestin 2 exerted an additive effect on resveratrol-reduced levels of p-Akt and p-GSK3 beta. Overexpression of beta-arrestin 2 decreased the percentage of apoptosis and caspase-3 activation and attenuated resveratrol-reduced levels of p-Akt and p-GSK3 beta. Taken together, our studies demonstrate for the first time that beta-arrestin 2 mediated signaling plays a critical role in resveratrol-induced apoptosis in EC cells. Major Conclusions: Resveratrol primes EC cells to undergo apoptosis by modulating beta-arrestin 2 mediated Akt/GSK3 beta signaling pathways. General significance: These inspiring findings would provide a new molecular basis for further understanding of cell apoptotic mechanisms mediated by beta-arrestin 2 and may provide insights into a potential clinical relevance in EC. (C) 2010 Elsevier B.V. All rights reserved.