Sorafenib inhibits hypoxia-inducible factor-1α synthesis: implications for anti-angiogenic activity in hepatocellular carcinoma
Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en inhibant l'expression des protéines VEGF et HIF-1α, le sorafenib exerce une action anti-angiogénique dans les carcinomes hépatocellulaires
Purpose:The overexpression of hypoxia-inducible factor (HIF)-1α is a common finding in hepatocellular carcinoma (HCC), and it leads to angiogenesis and poor prognosis. Sorafenib, a multikinase inhibitor, has demonstrated significant improvement in survival in patients with advanced HCC in clinical trials. However, the mechanisms that account for the anti-angiogenic efficiency of sorafenib have not been fully elucidated. The present study aims to explore the effect of sorafenib on HIF-1α expression and activation in HCC cells and xenografts. Experimental Design:HCC cells and xenografts were treated with sorafenib or vehicles. Western blotting and qPCR array were employed to determine protein and mRNA expression, respectively. HIF-1α activity, de novo protein synthesis and VEGF secretions were determined using assay kits. Results:Sorafenib dose-dependently decreased the hypoxia-induced accumulation and activation of HIF-1α protein. Further analysis revealed that such reduction of HIF-1α was associated with the inhibition of HIF-1α protein synthesis rather than the promotion of HIF-1α protein degradation or the reduction of HIF-1α mRNA. Moreover, the phosphorylation levels of mTOR, ERK, p70S6K, RP-S6, 4E-BP1 and eIF4E were significantly suppressed by sorafenib. In vivo studies further confirmed the inhibitory effect of sorafenib on the expression of HIF-1α and VEGF proteins, leading to a decrease in tumor vascularisation and growth of the xenografts. Conclusions:Sorafenib-mediated inhibition of HIF-1α synthesis is associated with previously undefined pathways in which mTOR/p70S6K/4E-BP1 and ERK phosphorylation are downregulated. Our preclinical data expand our understanding of sorafenib's anti-angiogenic mechanism of action by inhibiting HIF-1α and VEGF protein expression.