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

Abstract

Overexpression of hypoxia-induced factor 1' (HIF-1') has been shown to be involved in the development and progression of hepatocellular carcinoma (HCC). HIF-1' 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-1' and oxygen metabolism in HCC. The results showed that metformin inhibited hypoxia-induced HIF-1' accumulation and activation independent of AMP-activated protein kinase (AMPK). Moreover, this decrease in HIF- 1' accumulation was accompanied by promotion of HIF-1' 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-1' in HCC tumor xenografts. Together, these findings suggest that metformin decreases hypoxia-induced HIF-1' accumulation by actively suppressing mitochondrial oxygen consumption and enhancing cellular oxygenation ability, providing a fundamental mechanism of metformin activity against HCC.