title: Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Department of Respiratory Medicine and Cancer Center, The 5th Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Xinke
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Respiratory Medicine and Cancer Center, The 5th Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.|Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Jitao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Respiratory Medicine and Cancer Center, The 5th Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Gao
authors.initials: G
authors.lastname: Yi
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine and Cancer Center, The 5th Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Liang
authors.affiliation: Department of Respiratory Medicine and Cancer Center, The 5th Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Boyun
authors.initials: B
authors.lastname: Shi
authors.affiliation: State Key Laboratory of Respiratory Disease, The 1st Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Respiratory Disease, The 1st Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Respiratory Medicine and Cancer Center, The 5th Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.|Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Liangcai
authors.initials: L
authors.lastname: Chen
authors.affiliation: Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: He
authors.affiliation: State Key Laboratory of Respiratory Disease, The 1st Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine and Cancer Center, The 5th Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.|Cancer Hospital and Cancer Research Institute, Guangzhou Medical University, Guangzhou, PR China.
authors.forename: Jifang
authors.initials: J
authors.lastname: Liu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010100:Oxygen / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D007004:Hypoglycemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; D010100:Oxygen
keywords: HIF-1α; hepatocellular carcinoma; hypoxia; metabolic reprogramming; metformin