Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC

Nat Commun. 2012 May 29;3:865. doi: 10.1038/ncomms1859.

Abstract

Diabetic patients treated with metformin have a reduced incidence of cancer and cancer-related mortality. Here we show that metformin affects engraftment and growth of breast cancer tumours in mice. This correlates with the induction of metabolic changes compatible with clear anticancer effects. We demonstrate that microRNA modulation underlies the anticancer metabolic actions of metformin. In fact, metformin induces DICER expression and its effects are severely impaired in DICER knocked down cells. Conversely, ectopic expression of DICER recapitulates the effects of metformin in vivo and in vitro. The microRNAs upregulated by metformin belong mainly to energy metabolism pathways. Among the messenger RNAs downregulated by metformin, we found c-MYC, IRS-2 and HIF1alpha. Downregulation of c-MYC requires AMP-activated protein kinase-signalling and mir33a upregulation by metformin. Ectopic expression of c-MYC attenuates the anticancer metabolic effects of metformin. We suggest that DICER modulation, mir33a upregulation and c-MYC targeting have an important role in the anticancer metabolic effects of metformin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use*
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Cell Hypoxia / physiology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chromatin Immunoprecipitation
  • Female
  • Humans
  • Immunohistochemistry
  • Magnetic Resonance Spectroscopy
  • Metformin / pharmacology*
  • Metformin / therapeutic use*
  • Mice
  • Mice, Nude
  • Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Wound Healing / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antitubercular Agents
  • Metformin

Associated data

  • GEO/GSE37038