Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC.
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.
Translational Oncogenomics Unit, Italian National Cancer Institute, Rome, Italy. blandino@ifo.it
Giovanni
G
Blandino
Mariacristina
M
Valerio
Mario
M
Cioce
Federica
F
Mori
Luca
L
Casadei
Claudio
C
Pulito
Andrea
A
Sacconi
Francesca
F
Biagioni
Giancarlo
G
Cortese
Sergio
S
Galanti
Cesare
C
Manetti
Gennaro
G
Citro
Paola
P
Muti
Sabrina
S
Strano
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D009682:Magnetic Resonance Spectroscopy; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000995:Antitubercular Agents; D008687:Metformin