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.
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Authors | Laura Rosanò, Francesca Spinella, Giulia Genovesi, Valeriana Di Castro, Pier Giorgio Natali, Anna Bagnato |
Journal | Journal of cardiovascular pharmacology
(J Cardiovasc Pharmacol)
Vol. 44 Suppl 1
Pg. S136-9
(Nov 2004)
ISSN: 1533-4023 [Electronic] United States |
PMID | 15838263
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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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
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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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