Endothelin-B receptor blockade inhibits molecular effectors of melanoma cell progression.
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.
Rosanò
Laura
L
Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Rome, Italy.
Spinella
Francesca
F
Genovesi
Giulia
G
Di Castro
Valeriana
V
Natali
Pier Giorgio
PG
Bagnato
Anna
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018450:Disease Progression; D015536:Down-Regulation; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D019334:Endothelin-3 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D051178:alpha Catenin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D000970:Antineoplastic Agents; C079671:CTNNA2 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D015815:Cell Adhesion Molecules; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D009842:Oligopeptides; D010880:Piperidines; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D051178:alpha Catenin; D051176:beta Catenin; C086539:BQ 788