Endothelin-1 production and decreased endothelin B receptor expression in advanced prostate cancer

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.