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.

• Authors: Anna Bagnato, Laura Rosanò, Francesca Spinella, Valeriana Di Castro, Raffaele Tecce, Pier Giorgio Natali
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 4 Pg. 1436-43 (Feb 15 2004) ISSN: 0008-5472 [Print] United States
• PMID: 14973117 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• A 192621
• Cadherins
• Endothelin B Receptor Antagonists
• Endothelin-1
• Endothelin-3
• Pyrrolidines
• Receptor, Endothelin B
• Mitogen-Activated Protein Kinases
• Matrix Metalloproteinases, Membrane-Associated
• Metalloendopeptidases
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9

Topics

• Animals
• Cadherins (analysis)
• Cell Communication (drug effects)
• Cell Line, Tumor
• Endothelin B Receptor Antagonists
• Endothelin-1 (pharmacology)
• Endothelin-3 (pharmacology)
• Enzyme Activation
• Female
• Humans
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Matrix Metalloproteinases, Membrane-Associated
• Melanoma (drug therapy, metabolism, pathology)
• Metalloendopeptidases (metabolism)
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinases (metabolism)
• Pyrrolidines (pharmacology)
• Receptor, Endothelin B (physiology)
• Signal Transduction