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      Metformin inhibits melanoma development through autophagy and apoptosis mechanisms

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          Metformin is the most widely used antidiabetic drug because of its proven efficacy and limited secondary effects. Interestingly, recent studies have reported that metformin can block the growth of different tumor types. Here, we show that metformin exerts antiproliferative effects on melanoma cells, whereas normal human melanocytes are resistant to these metformin-induced effects. To better understand the basis of this antiproliferative effect of metformin in melanoma, we characterized the sequence of events underlying metformin action. We showed that 24 h metformin treatment induced a cell cycle arrest in G0/G1 phases, while after 72 h, melanoma cells underwent autophagy as demonstrated by electron microscopy, immunochemistry, and by quantification of the autolysosome-associated LC3 and Beclin1 proteins. In addition, 96 h post metformin treatment we observed robust apoptosis of melanoma cells. Interestingly, inhibition of autophagy by knocking down LC3 or ATG5 decreased the extent of apoptosis, and suppressed the antiproliferative effect of metformin on melanoma cells, suggesting that apoptosis is a consequence of autophagy. The relevance of these observations were confirmed in vivo, as we showed that metformin treatment impaired the melanoma tumor growth in mice, and induced autophagy and apoptosis markers. Taken together, our data suggest that metformin has an important impact on melanoma growth, and may therefore be beneficial in patients with melanoma.

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          Most cited references 31

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          AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.

          Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell-cycle arrest. AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell cycle that coordinates cellular proliferation with carbon source availability.
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              Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner.

              Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. Consistent with these observations, in two distinct preclinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.

                Author and article information

                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                September 2011
                01 September 2011
                1 September 2011
                : 2
                : 9
                : e199
                [1 ]INSERM U895, team 1, Centre Méditerranéen de Médecine Moléculaire (C3 M), équipe 1: Biologie et pathologies des cellules mélanocytaires, Bâtiment Archimed , Nice, France
                [2 ]Université de Nice Sophia Antipolis, Faculté de Médecine, IFR50 , Nice, France
                [3 ]INSERM, U895, équipe 2: Mort cellulaire, différenciation et cancer , Nice, France
                [4 ]Centre Commun de Microscopie Appliquée, Faculté des Sciences, Parc Valrose , Nice, France
                [5 ]Centre Hospitalier Universitaire de Nice, Hopital l'Archet, Service de Dermatologie , Nice, France
                [6 ]Centre Hospitalier Universitaire de Nice, Hopital l'Archet, Chirurgie générale et Cancérologie Digestive , Nice, France
                Author notes
                [* ]INSERM U895, team 1, Centre Méditerranéen de Médecine Moléculaire (C3 M), équipe 1: Biologie et pathologies des cellules mélanocytaires, Bâtiment Archimed , 151 route de Saint Antoine de Ginestière, BP 2 3194, 06204 Nice cedex 3, France. Tel: +33 4 89 06 43 33; Fax: +33 4 89 06 42 21; E-mail: srocchi@ 123456unice.fr
                Copyright © 2011 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                Original Article

                Cell biology

                autophagy, melanoma, apoptosis, metformin


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