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

Bingxin Li1, Maojun Zhou2, Jue Wang1

  • 1Department of Hepatobiliary and Pancreatic Surgery, National Health Commission (NHC) Key Laboratory of Nanobiological Technology, Xiangya Hospital, Central South University, Changsha, China.

Frontiers in Oncology
|July 30, 2021
PubMed

Insights

Glycochenodeoxycholate (GCDA) promotes liver cancer cell survival and drug resistance by activating ERK1/2. Inhibiting ERK1/2 phosphorylation offers a potential therapeutic strategy for hepatocellular carcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Glycochenodeoxycholate (GCDA), a bile salt component, is implicated in gastrointestinal tumor carcinogenesis.
  • Hepatocellular carcinoma (HCC) exhibits resistance to chemotherapy, necessitating novel therapeutic targets.

Purpose of the Study:

  • To investigate the role of extracellular signal-regulated kinase 1/2 (ERK1/2) in GCDA-induced survival and drug resistance in HCC cells.
  • To explore potential therapeutic strategies targeting the ERK1/2 pathway for liver cancer treatment.

Main Methods:

  • RNA interference was used to silence ERK1/2 expression in HCC cells.
  • PD98059, an ERK1/2 phosphorylation inhibitor, was employed to assess its effects on GCDA-treated cells.
  • Western blotting and nuclear translocation assays were performed to analyze protein expression and localization.

Main Results:

  • ERK1/2 was highly expressed in liver cancer cells, and its silencing suppressed GCDA-stimulated survival and promoted apoptosis.
  • GCDA treatment enhanced chemoresistance in QGY-7703 HCC cells, accompanied by increased ERK1/2 phosphorylation.
  • PD98059 treatment impaired GCDA-mediated proliferation and chemoresistance by inhibiting ERK1/2 nuclear translocation and modulating Mcl-1 and Bim expression.

Conclusions:

  • ERK1/2 signaling is crucial for GCDA-mediated proliferation and chemoresistance in HCC.
  • Disrupting ERK1/2 phosphorylation or nuclear translocation presents a promising therapeutic approach for GCDA-related liver cancer.
  • Targeting the ERK1/2 pathway could overcome drug resistance in hepatocellular carcinoma treatment.
Keywords:
anti-apoptosis proteinsextracellular signal-regulated kinase 1/2glycochenodeoxycholatehepatocellular carcinoma cellspro-apoptotic proteins

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