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

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 alphavbeta3 and alpha2beta1 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 alpha-catenin and beta-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.
AuthorsLaura Rosanò, Francesca Spinella, Giulia Genovesi, Valeriana Di Castro, Pier Giorgio Natali, Anna Bagnato
JournalJournal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 44 Suppl 1 Pg. S136-9 (Nov 2004) ISSN: 1533-4023 [Electronic] United States
PMID15838263 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • CTNNA2 protein, human
  • CTNNB1 protein, human
  • Cadherins
  • Cell Adhesion Molecules
  • Endothelin B Receptor Antagonists
  • Endothelin-1
  • Endothelin-3
  • Oligopeptides
  • Piperidines
  • RNA, Messenger
  • Receptor, Endothelin B
  • alpha Catenin
  • beta Catenin
  • BQ 788
Topics
  • Antineoplastic Agents (pharmacology)
  • Cadherins (metabolism)
  • Cell Adhesion Molecules (genetics, metabolism)
  • Cell Line, Tumor
  • Disease Progression
  • Down-Regulation
  • Endothelin B Receptor Antagonists
  • Endothelin-1 (metabolism)
  • Endothelin-3 (metabolism)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Melanoma (genetics, metabolism, pathology)
  • Oligopeptides (pharmacology)
  • Piperidines (pharmacology)
  • RNA, Messenger (metabolism)
  • Receptor, Endothelin B (metabolism)
  • alpha Catenin (metabolism)
  • beta Catenin (metabolism)

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