Endothelin B Receptor Blockade Inhibits Dynamics of Cell Interactions and Communications in Melanoma Cell Progression

Abstract

Phenotypic and genotypic analyses of cutaneous melanoma have identified the endothelin B receptor (ET(B)R) as tumor progression marker, thus representing a potential therapeutic target. Here, we demonstrate that activation of ET(B)R by endothelin-1 (ET-1) and ET-3 leads to loss of expression of the cell adhesion molecule E-cadherin and associated catenin proteins and gain of N-cadherin expression. Exposure of melanoma cells to ET-1 leads to a 60% inhibition in intercellular communication by inducing phosphorylation of gap junctional protein connexin 43. Additionally, activation of the ET(B)R pathway increases alpha(v)beta(3) and alpha(2)beta(1) integrin expression and matrix metalloproteinase (MMP)-2 and MMP-9, membrane type-1-MMP activation, and tissue inhibitor MMP-2 secretion. The ET(B)R pathway results into the downstream activation of focal adhesion kinase and extracellular signal-regulated kinase 1/2 signaling pathways, which lead to enhanced cell proliferation, adhesion, migration, and MMP-dependent invasion. The small molecule A-192621, an orally bioavailable nonpeptide ET(B)R antagonist, significantly inhibits melanoma growth in nude mice. These findings demonstrate that ET-1 and ET-3 through ET(B)R activation trigger signaling pathways involved in events associated with disruption of normal host-tumor interactions and progression of cutaneous melanoma. Pharmacological interruption of ET(B)R signaling may represent a novel therapeutic strategy in the treatment of this malignancy.