Endothelin-1 production by prostate cancer cell lines is up-regulated by factors involved in cancer progression and down-regulated by androgens

BACKGROUND. Recent data demonstrate that endothelin-1 (ET-1) concentration increases in plasma of men with advanced, hormone-refractory prostate adeno carcinoma. In addition, ET-1 is involved in osteblastic remodelling and new bone formation, suggesting a role for this vasoactive peptide in the metas tatic progression of prostate cancer to the bone. METHODS. We investigated the regulation of ET-I expression in androgen-sens itive and insensitive prostate cancer cell lines by androgens and several f actors involved in progression of prostate cancer (EGF) and bone remodellin g (TGF beta -1, IL1-alpha and IGF-1). RESULTS. Northern analysis and radio immunoassay demonstrated that all the ET-1 pathways are tuned off in the andro-en-sensitive LNCaP cell line when compared to the androgen-insensitive PC-3 and DU145. In PC-3 cells transfec ted with a full-length androgen receptor expression vector (PC-3-AR), treat ment with androgens reduced gene expression and secretion of ET-I without a ffecting the gene expression of ET-3. Collectively, these data support a ro le for androgens in the regulation of ET-I production by prostate adenocarc inoma cells. In PC-3 and DU145 cells, ET-1 gene expression and secretion we re up-regulated by TGF beta -1, EGF and IL1-alpha, whereas IGF-1 was ineffe ctive. Conversely, none of the treatments affected ECE-1 or ET-3 gene expre ssion. CONCLUSIONS. In conclusion, ET-1 production by prostate adenocarcinoma cell s is downregulated by androgens and up-regulated by factors involved in tum our progression indicating a role for this peptide in the biology of prosta te cancer. In view of the role exerted by ET-I in the process of bone metas tasis, our data suggest the use of ET-1 receptor antagonists in the treatme nt of advanced prostate cancer. (C) 2001 Wiley-Liss, Inc.