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Cell Discov. 2017 Jul 4;3:17022. doi: 10.1038/celldisc.2017.22. eCollection 2017.

Metformin-induced ablation of microRNA 21-5p releases Sestrin-1 and CAB39L antitumoral activities.

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Molecular Chemoprevention Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
Oncogenomic and Epigenetic Unit, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
Department of Preventive & Predictive Medicine, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
Unit of Endocrinological Gynecology, Ospedale Sant'Anna di Torino, Turin, Italy.
SAFU, 'Regina Elena' National Cancer Institute, Rome, Italy.
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Epigénétique et Épigénomique des Carcinomes Hépathocellulaires Viro-Induits du Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Division of Medical Oncology A, Italian National Cancer Institute 'Regina Elena', Rome, Italy.
Department of Oncology, Juravinski Cancer Center, McMaster University, Hamilton, Ontario, Canada.


Metformin is a commonly prescribed type II diabetes medication that exhibits promising anticancer effects. Recently, these effects were found to be associated, at least in part, with a modulation of microRNA expression. However, the mechanisms by which single modulated microRNAs mediate the anticancer effects of metformin are not entirely clear and knowledge of such a process could be vital to maximize the potential therapeutic benefits of this safe and well-tolerated therapy. Our analysis here revealed that the expression of miR-21-5p was downregulated in multiple breast cancer cell lines treated with pharmacologically relevant doses of metformin. Interestingly, the inhibition of miR-21-5p following metformin treatment was also observed in mouse breast cancer xenografts and in sera from 96 breast cancer patients. This modulation occurred at the levels of both pri-miR-21 and pre-miR-21, suggesting transcriptional modulation. Antagomir-mediated ablation of miR-21-5p phenocopied the effects of metformin on both the clonogenicity and migration of the treated cells, while ectopic expression of miR-21-5p had the opposite effect. Mechanistically, this reduction in miR-21-5p enhanced the expression of critical upstream activators of the AMP-activated protein kinase, calcium-binding protein 39-like and Sestrin-1, leading to AMP-activated protein kinase activation and inhibition of mammalian target of rapamycin signaling. Importantly, these effects of metformin were synergistic with those of everolimus, a clinically relevant mammalian target of rapamycin inhibitor, and were independent of the phosphatase and tensin homolog status. This highlights the potential relevance of metformin in combinatorial settings for the treatment of breast cancer.


cancer metabolism; everolimus; mTOR; metformin; miRNA

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