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

Abstract

Glycochenodeoxycholate (GCDA), a toxic component in bile salts, is involved in carcinogenesis of gastrointestinal tumors. The objective of this research was to study the function of ERK1/2 in the GCDA-mediated survival and drug-resistance in hepatocellular carcinoma cells (HCCs). Firstly, extracellular signal-regulated kinase 1/2 (ERK1/2) was detected extensively expressed in liver cancer cells, and silencing ERK1/2 by RNA interference could suppress GCDA-stimulated survival and promote apoptosis. Furthermore, phosphorylation of endogenous ERK1/2 could be potently stimulated by GCDA in combination with enhanced chemoresistance in QGY-7703 hepatocellular carcinoma cells. The GCDA-mediated proliferation and chemoresistance could be impaired by PD98059, which acted as an inhibitor to block the phosphorylation of ERK1/2. Mechanistically, PD98059 was able to potently suppress GCDA-stimulated nuclear aggregation of ERK1/2 and p-ERK1/2, upregulate pro-survival protein Mcl-1 and downregulate pro-apoptotic protein Bim. The results of this study indicated that disruption of ERK1/2 by blocking phosphorylation or nuclear translocation may put forward new methods for solving the problem of GCDA-related proliferation and drug-resistance in liver cancer treatment.

A bile acid-related prognostic signature in hepatocellular carcinoma

“…In the pathogenesis of HCC, ERK1, but not ERK2, phosphorylated intestine-specific homeobox, resulting to its nuclear translocation and the expression of downstream genes related to cell proliferation, malignant transformation and the resistance to sorafenib 34 . The expression and activation of MAPK3 were upregulated in HCC tissues and cells 35 , 36 . In line with this, our results indicated that MAPK3 were highly expressed in HCC.…”

Research Progress of Plant-Derived Natural Products against Drug-Resistant Cancer

“…Meanwhile, studies have shown that activation of the p38 pathway can lead to cell cycle arrest and apoptosis [ 212 ]. Activation of JNK can upregulate the expression of pro-apoptotic proteins and activate caspase 3 [ 213 ], while inhibition of ERK can promote cell apoptosis and inhibit the proliferation of tumor cells [ 214 ]. p38 MAPK can be activated by upstream signals involved in the control of various stress responses and DNA damage—for example, cell cycle arrest, mitochondrial damage, and apoptosis [ 215 ].…”