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

Giovanni Blandino (), Mariacristina Valerio, Mario Cioce, Federica Mori, Luca Casadei, Claudio Pulito, Andrea Sacconi, Francesca Biagioni, Giancarlo Cortese, Sergio Galanti, Cesare Manetti, Gennaro Citro, Paola Muti and Sabrina Strano
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Giovanni Blandino: Translational Oncogenomics Unit, Italian National Cancer Institute
Mariacristina Valerio: University of Rome 'La Sapienza'
Mario Cioce: Translational Oncogenomics Unit, Italian National Cancer Institute
Federica Mori: Molecular Chemoprevention Unit, Italian National Cancer Institute
Luca Casadei: University of Rome 'La Sapienza'
Claudio Pulito: Molecular Chemoprevention Unit, Italian National Cancer Institute
Andrea Sacconi: Translational Oncogenomics Unit, Italian National Cancer Institute
Francesca Biagioni: Translational Oncogenomics Unit, Italian National Cancer Institute
Giancarlo Cortese: Regina Elena Cancer Institute
Sergio Galanti: Translational Oncogenomics Unit, Italian National Cancer Institute
Cesare Manetti: University of Rome 'La Sapienza'
Gennaro Citro: Regina Elena Cancer Institute
Paola Muti: Juravinski Cancer Center-McMaster University Hamilton
Sabrina Strano: Molecular Chemoprevention Unit, Italian National Cancer Institute

Nature Communications, 2012, vol. 3, issue 1, 1-11

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms1859

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