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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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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. |
format | Online Article Text |
id | pubmed-4808039 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
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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