Cancer Therapy: Preclinical Sorafenib Inhibits Hypoxia-Inducible Factor-1a Synthesis: Implications for Antiangiogenic Activity in Hepatocellular Carcinoma

Purpose: The overexpression of hypoxia-inducible factor 1a (HIF-1a) is a common finding in hepatocellular carcinoma (HCC), and it leads to angiogenesis and poor prognosis. Sorafenib, a multikinase inhibitor, has shown significant improvement in survival in patients with advanced HCC in clinical trials. However, the mechanisms that account for the antiangiogenic efficiency of sorafenib have not been fully elucidated. The present study aims to explore the effect of sorafenib on HIF-1a expression and activation in HCC cells and xenografts. ExperimentalDesign:HCCcells and xenograftswere treatedwith sorafenib or vehicles.Western blotting and quantitative PCR array were used to determine protein and mRNA expression, respectively. HIF-1a activity, de novo protein synthesis, and VEGF secretions were determined using assay kits. Results: Sorafenibdose dependently decreased thehypoxia-induced accumulation andactivationofHIF1a protein. Further analysis revealed that such reduction of HIF-1a was associated with the inhibition of HIF-1a protein synthesis rather than the promotion of HIF-1a protein degradation or the reduction of HIF1a mRNA. Moreover, the phosphorylation levels of mTOR, extracellular signal-regulated kinase (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-1a and VEGF proteins, leading to a decrease in tumor vascularization and growth of the xenografts. Conclusions: Sorafenib-mediated inhibition ofHIF-1a synthesis is associatedwithpreviously undefined pathways in which mTOR/p70S6K/4E-BP1 and ERK phosphorylation are downregulated. Our preclinical data expandour understandingof sorafenib’s antiangiogenicmechanismof actionby inhibitingHIF-1a and VEGF protein expression. Clin Cancer Res; 18(20); 5662–71. 2012 AACR.