Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells

Abstract

Background This research aims to examine the mechanism of glycochenodeoxycholate (GCDA)-mediated survival and drug-resistance in hepatocellular carcinoma cells (HCC). Extracellular signal-regulated kinase 1/2 (ERK1/2) were extensively expressed in liver cancer cells.Methods GCDA-induced survival of human liver carcinoma cells and chemoresistance was determined by CCK8 and flow cytometry, respectively. Functional of ERK1/2 and interaction of Bcl-2 family members was determined in western blot and immunofluorescence.Results Silencing ERK1/2 by RNA interference suppressed GCDA-stimulated survival and promoted apoptosis. Furthermore, phosphorylation of endogenous ERK1/2 could be potently stimulated by GCDA in combination with enhanced chemoresistance in QGY-7703 hepatocellular carcinoma cells. And such GCDA-mediated proliferation and chemoresistance could be impaired by PD98059, who acts as an inhibitor to block phosphorylation of ERK1/2. Mechanistically, PD98059 was able to potently suppress GCDA-stimulated nuclear aggregation of ERK1/2 and p-ERK1/2, up-regulation of pro-survival protein Mcl-1 and decrease of pro-apoptotic protein Bim.Conclusions Our work verified the function of ERK1/2 in GCDA-induced chemoresistance in hepatocellular carcinoma cells. Disruption of ERK1/2 by blocking phosphorylation or nuclear translocation may put forward new methods for treating of GCDA-related proliferation and drug-resistance in liver cancer.