Endothelin receptor blockade inhibits proliferation of Kaposi's sarcoma cells.
Endothelin-1 (ET-1) has been shown to be mitogenic for endothelial and several tumor cells through an autocrine mechanism. In this study we evaluated whether the tumorigenic KS IMM cell line deriving from Kaposi's sarcoma (KS), a highly angiogenic tumor, is susceptible to ET-1 mitogenic activity. By reverse transcriptase-polymerase chain reaction, we detected ET-1 mRNA expression and both ET(A) receptor (ET(A)R) and ET(B)R mRNA transcripts in the KS IMM cells. High concentrations of ET-1 are released from the KS IMM cells and competition-binding studies demonstrated that these cells also express functional ET(A)R and ET(B)R with high affinity for ET-1 and ET-1/ET-3, respectively. Expression of ET-1 and cognate receptors could be detected by immunohistochemical method in vitro, in KS IMM xenograft, and in tissue sections of a human KS lesion. Furthermore ET-1 induces a marked and dose-dependent increase in [3H]thymidine incorporation comparable to that elicited by vascular endothelial growth factor. Addition of both selective ET(B)R antagonist (BQ 788) and ET(A)R antagonist (BQ 123), completely blocked ET-1-induced mitogenic response and reduced the basal growth rate of unstimulated cells, suggesting that both receptors mediated the proliferative signal. Such findings demonstrate that ET-1 participates on KS pathogenesis acting as an autocrine growth factor and that ET-1 receptor antagonists may thus be novel candidates for therapeutic intervention.
Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy. bagnato@ifo.it
A
A
Bagnato
L
L
Rosanò
V
V
Di Castro
A
A
Albini
D
D
Salani
M
M
Varmi
M R
MR
Nicotra
P G
PG
Natali
D000818:Animals; D019898:Autocrine Communication; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000235:genetics; D012514:Sarcoma, Kaposi / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D020033:Protein Isoforms; D017466:Receptors, Endothelin; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)