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Metformin inhibits hepatocellular carcinoma development by inducing apoptosis and pyroptosis through regulating FOXO3

Zetian Shen1,2, Han Zhou2, Aomei Li2

  • 1The Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing 210009, Jiangsu, China.

Aging
|September 21, 2021
PubMed

Insights

Metformin (Met) inhibits liver cancer (HCC) growth by promoting cell death (apoptosis and pyroptosis). This effect is partly mediated by FOXO3, a protein that activates NLRP3, influencing tumor progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Hepatocellular carcinoma (HCC) remains a significant global health challenge with limited effective therapeutic options.
  • Metformin (Met), a widely used antidiabetic drug, has shown potential anticancer properties, but its precise mechanisms in HCC are not fully elucidated.

Purpose of the Study:

  • To investigate the inhibitory effects of metformin on hepatocellular carcinoma (HCC) progression.
  • To elucidate the underlying molecular mechanisms, focusing on the role of FOXO3 and NLRP3 in metformin's action.

Main Methods:

  • Metformin was administered to HCC cells at varying concentrations (5, 10, 20 μM) to evaluate phenotypic changes.
  • RNA-sequencing (RNA-seq) was employed to identify target genes modulated by metformin.
  • Luciferase activity and Chromatin Immunoprecipitation (ChIP) assays were utilized to assess FOXO3's transcriptional activation of NLRP3.
  • In vitro and in vivo studies, including cell proliferation, apoptosis, pyroptosis assays, colony formation, migration assays, and tumor growth evaluations in animal models, were conducted.

Main Results:

  • Metformin significantly inhibited HCC cell proliferation and induced apoptosis and pyroptosis.
  • Metformin upregulated FOXO3 expression, which in turn activated the transcription of NLRP3.
  • Knockdown of FOXO3 in metformin-treated cells resulted in increased colony formation and migration, and reduced apoptosis, indicating a partial dependence of metformin's effect on FOXO3.
  • In vivo, metformin suppressed HCC tumor growth, and concurrent FOXO3 knockdown accelerated tumor growth compared to metformin treatment alone.

Conclusions:

  • Metformin attenuates hepatocellular carcinoma cell development through the induction of apoptosis and pyroptosis.
  • The observed anticancer effects of metformin are partially mediated by the FOXO3-NLRP3 pathway, highlighting a novel therapeutic mechanism.
Keywords:
FOXO3NLRP3hepatocellular carcinomametforminpyroptosis

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