Abstract
Abstract Metformin, a widely used and well-tolerated antidiabetic drug, may reduce cancer risk and improve prognosis of certain malignancies. In vitro and in vivo studies on several cancer models have evaluated the potential antitumorigenic effects of metformin and many clinical trials are looking to its use for suppressing tumor growth. However, the mechanism for its anti-cancer effect remains uncertain and needs to be clarified. Here we investigated the anti-cancer activity of metformin on colorectal cancer growth by treating three colorectal cancer cell lines, HT29, HCT116, HCT116p53-/-, with the drug. We found that, at a dose of 5mM, metformin reduced cell proliferation in all the colorectal cancer cells analyzed, as shown by BrdU incorporation assays. Metformin induced cell cycle arrest in G0/G1 phase that was accompanied by a strong decrease of cyclin D1, c-Myc expression, and inhibition of pRB phosphorylation. The antiproliferative activity of the drug resulted mediated by suppression of mTOR and IGF-1/AKT pathways. In particular, we observed inactivation of mTOR and of its downstream targets S6 and 4EBP1, both in an AMPK dependent and independent way, and also downregulation of the activity of IGF1R. We analysed the biological mechanisms by which metformin inhibited cell proliferation by evaluating its ability to induce apoptosis, autophagy or senescence, as observed in other cancer cell lines. Unexpectedly, we found that metformin did not stimulate any of these mechanisms in colorectal cancer cells. In support of these results, a colony formation assay showed that metformin did not arrest growth of cells, but only slowed down cell ability of forming colonies. Our findings highlight that metformin inhibits the proliferation of colorectal cancer cell lines as a consequence of promoting cell cycle arrest in the G0/G1 phase, but does not induce cell death. Further investigations are needed to better elucidate the mechanisms altered by the drug in colorectal cancer and caution should be used when treating cancer patients with metformin. Citation Format: Angela Mogavero, Maria Valeria Maiorana, Claudia Bertan, Fabio Bozzi, Marco A. Pierotti, Manuela Gariboldi. Metformin has an inhibitory effect on cell proliferation but does not induce death in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1161. doi:10.1158/1538-7445.AM2015-1161
Published Version
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