Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma.
Metformin suppresses hypoxia-induced stabilization of HIF-1α through reprogramming of oxygen metabolism in hepatocellular carcinoma.
复制标题
二甲双胍通过肝细胞癌氧代谢的重编程抑制缺氧诱导的 HIF-1α 稳定
DOI：
10.18632/oncotarget.6418
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发表时间：
2016-01-05
期刊：
影响因子：
--
通讯作者：
Liu J
中科院分区：
文献类型：
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作者：
Zhou X;Chen J;Yi G;Deng M;Liu H;Liang M;Shi B;Fu X;Chen Y;Chen L;He Z;Wang J;Liu J
低氧诱导因子1α (HIF-1α)的过表达参与了肝细胞癌（HCC）的发生和发展。因此，HIF-1α应该是开发抗hcc药物的一个有希望的分子靶点。二甲双胍是一种公认的抗糖尿病药物，已被证明对治疗癌症也有效，尽管这种活性的确切潜在机制尚未完全阐明。本研究旨在探讨二甲双胍对HCC中HIF-1α表达及氧代谢的影响。结果表明，二甲双胍抑制缺氧诱导的HIF-1α积累和不依赖于amp活化蛋白激酶（AMPK）的激活。此外，HIF-1α积累的减少伴随着HIF-1α蛋白降解的促进。此外，二甲双胍显著降低耗氧量，最终导致细胞内氧张力升高，缺氧标志物吡莫硝唑染色降低。体内研究表明，二甲双胍延缓肿瘤生长，并降低肝癌肿瘤异种移植物中HIF-1α的表达。总之，这些发现表明，二甲双胍通过积极抑制线粒体耗氧量和增强细胞氧合能力来降低缺氧诱导的HIF-1α积累，提供了二甲双胍抗HCC活性的基本机制。
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.