Phosphorylation of Bcl-2 Plays an Important Role in Glycochenodeoxycholate-induced Survival and Chemoresistance in HCC

Hepatocellular carcinoma (HCC) is a highly malignant tumor and can evolve rapidly to resistance to chemotherapies. Glycochenodeoxycholate (GCDA), which is toxic and hydrophobic, is the main ingredient in the bile and associated with carcinogenesis of gastrointenstinal tumors. Bcl-2 is the most important anti-apoptotic protein and overexpressed in various human tumors. In the present study, we found that GCDA can induce the chemoresistance of human liver cancer cells and specific depletion of Bcl-2 by RNA interference blocks GCDA-stimulated chemoresistance, which indicate the pivotal role of Bcl-2 in such process. Mechanistically, GCDA simultaneously stimulates phosphorylation of Bcl-2 at Ser70 site and activates extracellular signal-regulated kinase 1/2 (ERK1/2), and inhibition of ERK1/2 by PD98059 (MAPK/ERK1/2 inhibitor) or siRNA (targeting ERK1/2) suppresses GCDA-stimulated phosphorylation of Bcl-2 and significantly attenuates the survival and chemoresistance induced by GCDA in liver cancer cells. Thus, GCDA-induced survival and chemoresistance of liver cancer cells may occur through activation of Bcl-2 by phosphorylation at Ser70 site through MAPK/ERK1/2 pathway, which may contribute to the development of human liver cancer and chemoresistance.