The potent vasoconstrictor endothelin-1 (ET-1) is at its highest concentration in the normal human ejaculate and is associated with the progression of metastatic prostate cancer. ET-1 protein expression is detected in situ in 14 of 14 primary cancers and 14 of 16 metastatic sites of human prostatic carcinoma. Exogenous ET-1 induces prostate cancer proliferation directly and enhances the mitogenic effects of insulin-like growth factor I, insulin-like growth factor II, platelet-derived growth factor, basic fibroblast growth factor, and epidermal growth factor in serum-free conditions in vitro. The ET_A-selective receptor antagonist A-127722 inhibits ET-1-stimulated growth, but the ET_B-selective receptor antagonist BQ-788 does not. ET-3, an ET_B-selective agonist, also had no effect on prostate cancer growth. No specific ET_B-binding sites could be demonstrated in any established human prostate cancer cell line tested, and ET_B mRNA, detected by reverse transcription PCR, was reduced. The predominance of ET_B binding on human benign prostatic epithelial tissue is not present in metastatic prostate cancer by autoradiography. In human prostate cancer progression to metastases, ET-1 and ET_A expression are retained, whereas ET_B receptor expression is reduced.