Endothelin-1 induces the transactivation of vascular endothelial growth factor receptor-3 and modulates cell migration and vasculogenic mimicry in melanoma cells

作者：Spinella Francesca^*; Caprara Valentina; Di Castro Valeriana; Rosano Laura; Cianfrocca Roberta; Natali Pier Giorgio; Bagnato Anna

来源：Journal of Molecular Medicine-JMM, 2013, 91(3): 395-405.

DOI：10.1007/s00109-012-0956-2

• Endothelin B receptor
• Endothelin-1
• Vascular endothelial growth factor receptor-3
• Melanoma cells
• Hypoxia-inducible factor-alpha

Endothelin receptor B (ETBR) is a G-protein-coupled receptor overexpressed in melanoma, blood, and lymphatic endothelial cells. Given that aberrant signal transduction can be mediated through cross talk between receptors, here, we explore the functional relationship between ETBR and the vascular endothelial growth factor receptor (VEGFR)-3 system and how this cross talk might influence the aggressive behavior of melanoma cells. The expression of VEGFR-3 and its ligands, VEGF-C and VEGF-D, significantly increased after activating ETBR by ET-1 in primary and metastatic melanoma cell lines. These effects, similarly to those induced by hypoxia, were mediated by hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha. ET-1 caused the phosphorylation of VEGFR-3, which was accompanied by the activation of the downstream signaling molecules, such as MAPK and AKT. Inhibition of c-Src activity or silencing of the scaffold protein beta-arrestin-1 reduced ET-1-induced VEGFR-3 phosphorylation, demonstrating that, upon ET-1 stimulus, beta-arrestin-1 is involved with c-Src in the ETBR-mediated VEGFR-3 transactivation. Moreover, ET-1 in combination with VEGF-C further increased VEGFR-3, MAPK, and AKT phosphorylation and markedly promoted cell migration and vasculogenic mimicry. Dual inhibition of ETBR and VEGFR-3 was required for the effective inhibition of these effects, as well as for VEGFR-3 phosphorylation, demonstrating that ETBR cross talk with VEGFR-3 enhances cell plasticity and motility. Finally, in melanoma xenografts, ETBR antagonist inhibited tumor growth and the activation of the VEGF-C/VEGFR-3 axis, indicating that targeting ETBR may improve melanoma treatment acting directly or indirectly by impairing ETBR cross talk with VEGFR-3.

• 出版日期2013-3