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

Anna Bagnato, Laura Rosanò, Francesca Spinella, Valeriana Di Castro, Raffaele Tecce, Pier Giorgio Natali

Research output: Contribution to journalArticle

Abstract

Phenotypic and genotypic analyses of cutaneous melanoma have identified the endothelin B receptor (ETBR) as tumor progression marker, thus representing a potential therapeutic target. Here, we demonstrate that activation of ETBR 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 ETBR pathway increases αvβ3 and α2β1 integrin expression and matrix metalloproteinase (MMP)-2 and MMP-9, membrane type-1-MMP activation, and tissue inhibitor MMP-2 secretion. The ETBR 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 ETBR antagonist, significantly inhibits melanoma growth in nude mice. These findings demonstrate that ET-1 and ET-3 through ETBR activation trigger signaling pathways involved in events associated with disruption of normal host-tumor interactions and progression of cutaneous melanoma. Pharmacological interruption of ETBR signaling may represent a novel therapeutic strategy in the treatment of this malignancy.

Original languageEnglish
Pages (from-to)1436-1443
Number of pages8
JournalCancer Research
Volume64
Issue number4
DOIs
Publication statusPublished - Feb 15 2004

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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