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Metformin inhibits melanoma development through autophagy and apoptosis mechanisms

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,...

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Autores principales: Tomic, T, Botton, T, Cerezo, M, Robert, G, Luciano, F, Puissant, A, Gounon, P, Allegra, M, Bertolotto, C, Bereder, J-M, Tartare-Deckert, S, Bahadoran, P, Auberger, P, Ballotti, R, Rocchi, S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186904/
https://www.ncbi.nlm.nih.gov/pubmed/21881601
http://dx.doi.org/10.1038/cddis.2011.86
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author Tomic, T
Botton, T
Cerezo, M
Robert, G
Luciano, F
Puissant, A
Gounon, P
Allegra, M
Bertolotto, C
Bereder, J-M
Tartare-Deckert, S
Bahadoran, P
Auberger, P
Ballotti, R
Rocchi, S
author_facet Tomic, T
Botton, T
Cerezo, M
Robert, G
Luciano, F
Puissant, A
Gounon, P
Allegra, M
Bertolotto, C
Bereder, J-M
Tartare-Deckert, S
Bahadoran, P
Auberger, P
Ballotti, R
Rocchi, S
author_sort Tomic, T
collection PubMed
description 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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spelling pubmed-31869042011-11-21 Metformin inhibits melanoma development through autophagy and apoptosis mechanisms Tomic, T Botton, T Cerezo, M Robert, G Luciano, F Puissant, A Gounon, P Allegra, M Bertolotto, C Bereder, J-M Tartare-Deckert, S Bahadoran, P Auberger, P Ballotti, R Rocchi, S Cell Death Dis Original Article 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. Nature Publishing Group 2011-09 2011-09-01 /pmc/articles/PMC3186904/ /pubmed/21881601 http://dx.doi.org/10.1038/cddis.2011.86 Text en Copyright © 2011 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ 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/
spellingShingle Original Article
Tomic, T
Botton, T
Cerezo, M
Robert, G
Luciano, F
Puissant, A
Gounon, P
Allegra, M
Bertolotto, C
Bereder, J-M
Tartare-Deckert, S
Bahadoran, P
Auberger, P
Ballotti, R
Rocchi, S
Metformin inhibits melanoma development through autophagy and apoptosis mechanisms
title Metformin inhibits melanoma development through autophagy and apoptosis mechanisms
title_full Metformin inhibits melanoma development through autophagy and apoptosis mechanisms
title_fullStr Metformin inhibits melanoma development through autophagy and apoptosis mechanisms
title_full_unstemmed Metformin inhibits melanoma development through autophagy and apoptosis mechanisms
title_short Metformin inhibits melanoma development through autophagy and apoptosis mechanisms
title_sort metformin inhibits melanoma development through autophagy and apoptosis mechanisms
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186904/
https://www.ncbi.nlm.nih.gov/pubmed/21881601
http://dx.doi.org/10.1038/cddis.2011.86
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