Endothelin-B receptor blockade inhibits molecular effectors of melanoma cell progression

Laura Rosanò, Francesca Spinella, Giulia Genovesi, Valeriana Di Castro, Pier Giorgio Natali, Anna Bagnato

Research output: Contribution to journalArticle

Abstract

Expression of endothelin-B receptor gradually increases as melanocytic lesions progress to melanoma, suggesting that endothelin-B receptor and its ligands, endothelin-1 and endothelin-3, play a role in the melanoma progression. The selective blockade of endothelin-B receptor results in inhibition of focal adhesion kinase and mitogen-activated protein kinase phosphorylation and cell proliferation induced by endothelins in human melanoma cell lines. In these cells, endothelins induce downregulation of E-cadherin expression and concomitant upregulation of transcriptional factor Snail. Activation of the endothelin-B receptor pathway by endothelins also upregulates N-cadherin, phosphorylates the gap junctional protein connexin 43, increases αvβ3 and α2β1, integrin expression and tumor proteolytic activity, thus enhancing endothelin-B receptor-mediated cell adhesion, migration and invasiveness. In this study we demonstrated that activation of the endothelin-B receptor pathway by endothelin-1 and endothelin-3 contributes to disruption of normal host-tumor interactions by downregulating, at mRNA and protein levels, the expression of E-cadherin and associated α-catenin and β-catenin adhesion proteins, which are critical for E-cadherin function. A-192621, an orally active non-peptide endothelin-B receptor antagonist, significantly inhibited melanoma growth in nude mice, suggesting that the pharmacological interruption of endothelin-B receptor signaling by endothelin-B receptor antagonist may represent a new therapeutic approach in the treatment of cutaneous melanoma.

Original languageEnglish
JournalJournal of Cardiovascular Pharmacology
Volume44
Issue numberSUPPL. 1
DOIs
Publication statusPublished - Nov 2004

    Fingerprint

Keywords

  • Adhesion molecules
  • Endothelin (ET)
  • Endothelin-B (ET) receptor
  • Invasion
  • Melanoma

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this