The endothelin B receptor (ETBR) promotes tumorigenesis and melanoma progression through activation by endothelin (ET)-1, thus representing a promising therapeutic target. The stability of hypoxia-inducible factor (HIF)-1α is essential for melanomagenesis and progression. In melanoma cells cultured in normoxic conditions, ET-1, ET-2, and ET-3 through ETBR enhance HIF-1α and HIF-2α expression, and activity and both transcriptional factors regulate the expression of target genes, such as vascular endothelial growth factor (VEGF) and ET-1 in response to ETs or hypoxia. In turn, ETs control HIF-1α stability by inhibiting its degradation. In particular, ETs through ETBR markedly decrease prolyl hydroxylase domain (PHD)2 mRNA and protein levels and promoter activity. In addition, we found that activation of phosphatidylinositol 3-kinase (PI3K)-dependent integrin linked kinase (ILK)-AKT-mammalian target of rapamycin (mTOR) pathway is required for ETBR-mediated PHD2 inhibition, HIF-1α, HIF-2α, and VEGF expression. At functional level, PHD2 knockdown does not further increase ETs-induced angiogenesis and melanoma cell invasiveness demonstrating that these processes are regulated in a PHD2-dependent manner. In human primary and metastatic melanomas, that express high level of HIF-1α, ETBR expression is associated with low PHD2 levels. In melanoma xenografts, ETBR blockade by ETBR antagonist results in a concomitant reduction of angiogenesis, HIF-1α, HIF-2α and VEGF expression, and an increase in PHD2 levels. In conclusion, we identified the underlying mechanism by which ET-1 controls HIF-1α stability and thereby regulates angiogenesis and tumor invasion through the regulation of PHD2. These results further indicate that targeting ETBR may represent a potential therapeutic treatment of melanoma by impairing HIF-1α stability. Supported by AIRC.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1286.