Metformin Targets Central Carbon Metabolism and Reveals Mitochondrial Requirements in Human Cancers.
Cell Metab
; 24(5): 728-739, 2016 11 08.
Article
em En
| MEDLINE
| ID: mdl-27746051
ABSTRACT
Repurposing metformin for cancer therapy is attractive due to its safety profile, epidemiological evidence, and encouraging data from human clinical trials. Although it is known to systemically affect glucose metabolism in liver, muscle, gut, and other tissues, the molecular determinants that predict a patient response in cancer remain unknown. Here, we carry out an integrative metabolomics analysis of metformin action in ovarian cancer. Metformin accumulated in patient biopsies, and pathways involving nucleotide metabolism, redox, and energy status, all related to mitochondrial metabolism, were affected in treated tumors. Strikingly, a metabolic signature obtained from a patient with an exceptional clinical outcome mirrored that of a responsive animal tumor. Mechanistically, we demonstrate with stable isotope tracing that these metabolic signatures are due to an inability to adapt nutrient utilization in the mitochondria. This analysis provides new insights into mitochondrial metabolism and may lead to more precise indications of metformin in cancer.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Carbono
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Metformina
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Mitocôndrias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article