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Metformin induces cell cycle arrest at the G1 phase through E2F8 suppression in lung cancer cells

Dong Hao Jin1, Yujin Kim1, Bo Bin Lee1

  • 1Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 440-746, Korea.

Oncotarget
|December 20, 2017
PubMed

Insights

Metformin halts lung cancer cell growth by reducing E2F8 expression, a key factor in cell cycle progression. E2F8 overexpression correlates with poorer survival in lung cancer patients.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Cycle Regulation

Background:

  • Metformin is a widely used antidiabetic drug with demonstrated anti-cancer properties.
  • The precise molecular mechanisms underlying metformin's anti-cancer effects, particularly in lung cancer, remain incompletely understood.
  • Identifying novel molecular targets is crucial for developing effective lung cancer therapies.

Purpose of the Study:

  • To identify the molecular target responsible for metformin-induced cell cycle arrest in lung cancer cells.
  • To investigate the role of E2F8 in mediating the effects of metformin on the cell cycle.
  • To assess the clinical significance of E2F8 expression in lung cancer patients.

Main Methods:

  • Gene chip array analysis to identify potential targets of metformin.
  • siRNA-mediated knockdown and ectopic expression of E2F8 to study its function.
  • Analysis of p21 mRNA levels and its relationship with E2F8.
  • Assessment of E2F8 mRNA degradation and the role of AMPK signaling.
  • Retrospective analysis of E2F8 mRNA expression in The Cancer Genome Atlas (TCGA) lung cancer dataset.

Main Results:

  • E2F8 was identified as a target molecule mediating metformin's effect on cell cycle arrest.
  • Knockdown of E2F8 suppressed G1-S phase progression, while its overexpression reversed metformin-induced arrest.
  • p21 mRNA levels were inversely correlated with E2F8, and p21 knockdown partially rescued E2F8 knockdown-induced cell cycle arrest.
  • Metformin did not affect E2F8 mRNA degradation, and AMPK signaling was not involved in E2F8 suppression.
  • E2F8 was overexpressed in 13% of lung cancers in the TCGA dataset and associated with significantly poorer overall survival.

Conclusions:

  • Metformin induces cell cycle arrest at the G1 phase in lung cancer cells, likely by suppressing E2F8 expression.
  • E2F8 overexpression is a potential biomarker for poor prognosis in lung cancer patients, independent of histological type.
Keywords:
E2F8cell cyclelung cancermetforminp21

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