Abstract 1286: Endothelin-1-induced angiogenesis is regulated by PHD2 in a HIF-1α-dependent manner

The endothelin B receptor (ET_BR) 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 ET_BR 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 ET_BR 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 ET_BR-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, ET_BR expression is associated with low PHD2 levels. In melanoma xenografts, ET_BR blockade by ET_BR 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 ET_BR 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.