Endothelin receptor blockade inhibits proliferation of Kaposi's sarcoma cells

Endothelin-1 (ET-1) has been shown to be mitogenic for endothelial and seve ral 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 exp ression and both ETA receptor (ETAR) and ETBR mRNA transcripts in the KS IM M cells. High concentrations of ET-1 are released from the KS IMM cells and competition-binding studies demonstrated that these cells also express fun ctional ETAR and ETBR with high affinity for ET-1 and ET-1/ ET-3, respectiv ely. Expression of ET-1 and cognate receptors could be detected by immunohi stochemical 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 in crease in [H-3]thymidine incorporation comparable to that elicited by vascu lar endothelial growth factor. Addition of both selective ETBR antagonist ( BQ 788) and ETAR antagonist (BQ 123), completely blocked ET-1-induced mitog enic response and reduced the basal growth rate of unstimulated cells, sugg esting that both receptors mediated the proliferative signal. Such findings demonstrate that ET-1 participates on KS pathogenesis acting as an autocri ne growth factor and that ET-1 receptor antagonists may thus be novel candi dates for therapeutic intervention.