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Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma

Overexpression of hypoxia-induced factor 1α (HIF-1α) has been shown to be involved in the development and progression of hepatocellular carcinoma (HCC). HIF-1α should therefore be a promising molecular target for the development of anti-HCC agents. Metformin, an established antidiabetic drug, has pr...

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Autores principales: Zhou, Xinke, Chen, Jitao, Yi, Gao, Deng, Min, Liu, Hao, Liang, Min, Shi, Boyun, Fu, Xin, Chen, Yuqin, Chen, Liangcai, He, Zhimin, Wang, Jian, Liu, Jifang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808039/
https://www.ncbi.nlm.nih.gov/pubmed/26621849
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author Zhou, Xinke
Chen, Jitao
Yi, Gao
Deng, Min
Liu, Hao
Liang, Min
Shi, Boyun
Fu, Xin
Chen, Yuqin
Chen, Liangcai
He, Zhimin
Wang, Jian
Liu, Jifang
author_facet Zhou, Xinke
Chen, Jitao
Yi, Gao
Deng, Min
Liu, Hao
Liang, Min
Shi, Boyun
Fu, Xin
Chen, Yuqin
Chen, Liangcai
He, Zhimin
Wang, Jian
Liu, Jifang
author_sort Zhou, Xinke
collection PubMed
description Overexpression of hypoxia-induced factor 1α (HIF-1α) has been shown to be involved in the development and progression of hepatocellular carcinoma (HCC). HIF-1α should therefore be a promising molecular target for the development of anti-HCC agents. Metformin, an established antidiabetic drug, has proved to also be effective in treating cancer although the precise underlying mechanisms of this activity are not fully elucidated. The aim of this study was to investigate the effects of metformin on the expression of HIF-1α and oxygen metabolism in HCC. The results showed that metformin inhibited hypoxia-induced HIF-1α accumulation and activation independent of AMP-activated protein kinase (AMPK). Moreover, this decrease in HIF-1α accumulation was accompanied by promotion of HIF-1α protein degradation. In addition, metformin significantly decreased oxygen consumption, ultimately leading to increased intracellular oxygen tension and decreased staining with the hypoxia marker pimonidazole. In vivo studies demonstrated that metformin delayed tumor growth and attenuated the expression of HIF-1α in HCC tumor xenografts. Together, these findings suggest that metformin decreases hypoxia-induced HIF-1α accumulation by actively suppressing mitochondrial oxygen consumption and enhancing cellular oxygenation ability, providing a fundamental mechanism of metformin activity against HCC.
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spelling pubmed-48080392016-04-19 Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma Zhou, Xinke Chen, Jitao Yi, Gao Deng, Min Liu, Hao Liang, Min Shi, Boyun Fu, Xin Chen, Yuqin Chen, Liangcai He, Zhimin Wang, Jian Liu, Jifang Oncotarget Research Paper Overexpression of hypoxia-induced factor 1α (HIF-1α) has been shown to be involved in the development and progression of hepatocellular carcinoma (HCC). HIF-1α should therefore be a promising molecular target for the development of anti-HCC agents. Metformin, an established antidiabetic drug, has proved to also be effective in treating cancer although the precise underlying mechanisms of this activity are not fully elucidated. The aim of this study was to investigate the effects of metformin on the expression of HIF-1α and oxygen metabolism in HCC. The results showed that metformin inhibited hypoxia-induced HIF-1α accumulation and activation independent of AMP-activated protein kinase (AMPK). Moreover, this decrease in HIF-1α accumulation was accompanied by promotion of HIF-1α protein degradation. In addition, metformin significantly decreased oxygen consumption, ultimately leading to increased intracellular oxygen tension and decreased staining with the hypoxia marker pimonidazole. In vivo studies demonstrated that metformin delayed tumor growth and attenuated the expression of HIF-1α in HCC tumor xenografts. Together, these findings suggest that metformin decreases hypoxia-induced HIF-1α accumulation by actively suppressing mitochondrial oxygen consumption and enhancing cellular oxygenation ability, providing a fundamental mechanism of metformin activity against HCC. Impact Journals LLC 2015-11-28 /pmc/articles/PMC4808039/ /pubmed/26621849 Text en Copyright: © 2016 Zhou et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Zhou, Xinke
Chen, Jitao
Yi, Gao
Deng, Min
Liu, Hao
Liang, Min
Shi, Boyun
Fu, Xin
Chen, Yuqin
Chen, Liangcai
He, Zhimin
Wang, Jian
Liu, Jifang
Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma
title Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma
title_full Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma
title_fullStr Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma
title_full_unstemmed Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma
title_short Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma
title_sort metformin suppresses hypoxia-induced stabilization of hif-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4808039/
https://www.ncbi.nlm.nih.gov/pubmed/26621849
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