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Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth

Monica Buzzai1, Russell G Jones, Ravi K Amaravadi

  • 1Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.

Cancer Research
|July 20, 2007
PubMed

Insights

The antidiabetic drug metformin selectively kills colon cancer cells lacking the p53 tumor suppressor gene. This occurs because metformin forces a metabolic shift that p53-deficient cells cannot perform, explaining reduced tumor incidence in patients on metformin.

Area of Science:

  • Oncology
  • Metabolic pathways
  • Cancer cell biology

Background:

  • Metformin is a widely used antidiabetic drug.
  • The tumor suppressor protein p53 plays a critical role in cellular response to stress.
  • The interplay between metformin, p53, and cancer metabolism is not fully understood.

Purpose of the Study:

  • To investigate the effect of metformin on tumor growth in a p53-dependent manner.
  • To elucidate the molecular mechanisms underlying metformin's selective toxicity to cancer cells.
  • To explore the role of AMP-activated protein kinase (AMPK) and metabolic reprogramming in metformin's action.

Main Methods:

  • Utilized paired isogenic colon cancer cell lines (HCT116 p53(+/+) and HCT116 p53(-/-)) for in vitro and in vivo studies.
  • Administered metformin and AICAR (an AMPK activator) to assess tumor growth, apoptosis, autophagy, and metabolic changes.
  • Analyzed tumor sections and cell cultures for apoptosis, autophagy markers, fatty acid beta-oxidation, and glycolysis rates.

Main Results:

  • Metformin selectively suppressed the growth of p53(-/-) colon cancer xenografts.
  • Increased apoptosis and enhanced susceptibility to apoptosis under nutrient deprivation were observed in p53(-/-) cells post-metformin treatment.
  • Metformin and AICAR induced autophagy in p53(+/+) cells but not in p53(-/-) cells, indicating p53-dependent autophagy activation.
  • Metformin treatment led to p53-dependent compensation for suppressed oxidative phosphorylation by increasing glycolysis.

Conclusions:

  • Metformin exhibits selective toxicity towards p53-deficient cancer cells by inducing a metabolic crisis.
  • The p53 protein is crucial for mediating adaptive metabolic responses to metformin, including autophagy and glycolysis.
  • These findings suggest a potential mechanism for the observed reduction in tumor incidence in patients treated with metformin.

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