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Metformin promotes apoptosis in hepatocellular carcinoma through the CEBPD-induced autophagy pathway

Hsin-Hwa Tsai1, Hong-Yue Lai2, Yueh-Chiu Chen3

  • 1Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan.

Oncotarget
|January 19, 2017
PubMed

Insights

Metformin activates autophagy and promotes apoptosis in liver cancer cells by increasing CCAAT/enhancer-binding protein delta (CEBPD) expression. This study reveals a novel therapeutic strategy targeting autophagy for hepatocellular carcinoma (HCC) treatment.

Area of Science:

  • Molecular Oncology
  • Cellular Biology
  • Pharmacology

Background:

  • Metformin, an AMP-activated protein kinase (AMPK) activator, is known to induce autophagy and has been linked to reduced hepatocellular carcinoma (HCC) risk in diabetic patients.
  • The precise mechanisms underlying metformin's anticancer effects, particularly in HCC, remain incompletely understood.
  • CCAAT/enhancer-binding protein delta (CEBPD) functions as a tumor suppressor in HCC and responds to various anticancer agents.

Purpose of the Study:

  • To elucidate the detailed molecular mechanisms of metformin's anticancer effect in HCC, focusing on CEBPD and autophagy.
  • To investigate the role of CEBPD and autophagy in metformin-induced apoptosis in Huh7 HCC cells.
  • To explore the involvement of AMPK in metformin-mediated CEBPD expression and its impact on autophagy.

Main Methods:

  • Investigated metformin's effects on CEBPD expression, protein degradation, and autophagy markers (LC3B, ATG3) in Huh7 cells.
  • Utilized techniques to assess Src-mediated CEBPD degradation and CEBPD-regulated gene transcription.
  • Examined the role of AMPK in metformin-induced CEBPD expression and explored combined metformin and rapamycin treatment effects on autophagic cell death.

Main Results:

  • Metformin treatment led to increased apoptosis in Huh7 cells, involving both CEBPD and autophagy.
  • Mechanistically, metformin reduced Src-mediated CEBPD protein degradation and enhanced CEBPD-regulated transcription of LC3B and ATG3.
  • AMPK activation was found to be involved in metformin-induced CEBPD expression, and combined metformin-rapamycin treatment enhanced autophagic cell death via AMPK-dependent and independent pathways.

Conclusions:

  • Metformin promotes apoptosis in HCC cells through a mechanism involving CEBPD stabilization and autophagy activation.
  • The study highlights the critical roles of CEBPD and autophagy in mediating metformin's anti-cancer effects in HCC.
  • Targeting autophagy presents a promising therapeutic avenue for HCC treatment, potentially enhanced by combination therapies involving metformin.
Keywords:
CEBPDHCCapoptosisautophagymetformin

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