title: Metformin inhibits melanoma development through autophagy and apoptosis mechanisms.
abstract: 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.
authors: INSERM U895, team 1, Centre Méditerranéen de Médecine Moléculaire (C3 M), équipe 1: Biologie et pathologies des cellules mélanocytaires, Bâtiment Archimed, Nice, France.
authors: T
authors: T
authors: Tomic
authors: T
authors: T
authors: Botton
authors: M
authors: M
authors: Cerezo
authors: G
authors: G
authors: Robert
authors: F
authors: F
authors: Luciano
authors: A
authors: A
authors: Puissant
authors: P
authors: P
authors: Gounon
authors: M
authors: M
authors: Allegra
authors: C
authors: C
authors: Bertolotto
authors: J-M
authors: JM
authors: Bereder
authors: S
authors: S
authors: Tartare-Deckert
authors: P
authors: P
authors: Bahadoran
authors: P
authors: P
authors: Auberger
authors: R
authors: R
authors: Ballotti
authors: S
authors: S
authors: Rocchi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D045744:Cell Line, Tumor; D016193:G1 Phase; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology* / Q000633:toxicity*; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D014183:Transplantation, Heterologous
chemical_list: C502778:ATG5 protein, human; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D008687:Metformin