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.