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.

Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

“…Metformin reduced levels of HIF‐1α mRNA and protein in hepatocellular and squamous cancer cells . Metformin reduced HIF‐1α protein levels by suppressing mitochondrial respiration thereby reducing cellular hypoxia . Metformin improved diastolic function in diabetic rats .…”

“…128 Metformin reduced HIF-1α protein levels by suppressing mitochondrial respiration thereby reducing cellular hypoxia. 129 Metformin improved diastolic function in diabetic rats. 130 Analysis of the REACH patient registry demonstrated a 24% reduction in heart failure related mortality in patients taking metformin.…”

Repurposing metformin for cancer treatment: current clinical studies

“…In-vivo studies on hepatocellular carcinoma xenografts have shown that metformin improves cellular oxygenation ability and decreases mitochondrial oxygen consumption, thus suppressing hypoxia-induced HIF-1α accumulation. These effects form the basis of anti-cancer activity of metformin, particularly against hepatocellular carcinoma [18]. …”

Antitumor effects of circ‐EPHB4 in hepatocellular carcinoma via inhibition of HIF‐1α

“…32,33 Thus, the AMPK-mTOR could be affected and lead to cell cycle arrest and apoptosis. 34 In fact, molecular or even therapeutic treatment of HCC by inhibiting HIF-1α, such as HSP90 35 and Metformin, 36 The epithelial-mesenchymal transition (EMT) is a morphogenetic process that results in a loss of epithelial characteristics and acquisition of a mesenchymal phenotype and has become one of the most exciting and increasingly investigated areas in the oncology field. [37][38][39] During the process, ZEB1 and E-box-binding transcription factors are reportedly involved in the tumorigenesis of various malignancies.…”