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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most prevalent fatal cancers worldwide and the second leading cause of death in China
HIF-1α protein was undetectable in HepG2 cells under normoxia, but its expression markedly increased under hypoxia
We showed that metformin decreases hypoxia-induced HIF-1α protein content by promoting protein degradation rather than through reduction of protein synthesis or mRNA transcription
Summary
Hepatocellular carcinoma (HCC) is one of the most prevalent fatal cancers worldwide and the second leading cause of death in China. Increasing evidence suggests that intratumor hypoxia is a common phenomenon of solid tumors, including HCC, and an important microenvironmental factor influencing development of a malignant phenotype [1]. HIF-1α has been found to be upregulated in a variety of human malignancies, leading to an increased capacity for metastasis and an unfavorable prognosis [3, 4]. Whereas HIF-1β is a constitutive nuclear protein, HIF-1α is tightly regulated according to oxygen availability through its protein stability. HIF-1α is stabilized and translocates to the nucleus, where it dimerizes with HIF-1β and activates the expression of a broad range of target genes including glucose transporter 1 (Glut1) and carbonic anhydrase IX (CAIX), facilitating tumorigenesis and cancer progression [6,7,8]
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