P28GANK inhibits endoplasmic reticulum stress-induced cell death via enhancement of the endoplasmic reticulum adaptive capacity

Abstract

It has been shown that oncoprotein p28GANK, which is consistently overexpressed in human hepatocellular carcinoma (HCC), plays a critical role in tumorigenesis of HCC. However, the underlying mechanism remains unclear. Here, we demonstrated that p28GANK inhibits apoptosis in HCC cells induced by the endoplasmic reticulum (ER) stress. During ER stress, p28GANK enhances the unfolded protein response, promotes ER recovery from translational repression, and thereby facilitates cell's ability to cope with the stress conditions. Furthermore, p28GANK upregulates glucose-regulated protein 78 (GRP78), a key ER chaperone protein, which subsequently enhances the ER folding capacity and promotes recovery from ER stress. We also demonstrated that p28GANK increases p38 mitogen-activated protein kinase and Akt phosphorylation, and inhibits nuclear factor kappa B (NF-κB) activation under ER stress, which in turn contributes to GRP78 upregulation. Taken together, our results indicate that p28GANK inhibits ER stress-induced apoptosis in HCC cells, at least in part, by enhancing the adaptive response and GRP78 expression. We propose that p28GANK has potential implications for HCC progression under the ER stress conditions. © 2009 IBCB, SIBS, CAS All rights reserved.