AbstractBACKGROUNDProsaposin overexpression and/or genomic amplification have been demonstrated in androgen‐independent (AI) prostate cancer cell lines and tissues. Here, we explored the possibility for a functional relationship between prosaposin and androgen receptor (AR) in LNCaP cells.METHODSThe effect of prosaposin or its active molecular derivatives (e.g., saposin C) on expression and activity of androgen receptor (AR) and prostate‐specific antigen (PSA) was examined by using immunoblotting, RT‐PCR, transfection, and reporter gene assays, immunofluorescence staining, and inhibitors of signal transduction pathways.RESULTSProsaposin or saposin C, in an AI‐manner, (a) increased AR mRNA and protein expression and nuclear AR content and its phosphorylation state; (b) increased PSA mRNA and protein expression; and (c) upregulated PSA‐ and an androgen‐inducible probasin (PB)‐reporter gene activity in LNCaP and AR‐transfected PC‐3 cells. Induction of PSA expression and reporter activity was substantially blocked or prevented with the antiandrogen bicalutamide, pertussis toxin, or inhibitors of MAPK‐ and PI3K/Akt‐signaling pathways, indicating an androgen‐agonistic effect for saposin C that involves AR and multiple signaling pathways.CONCLUSIONSThe results for the first time introduce prosaposin as an androgen‐agonist in prostate cancer cells. This finding, together with the growth‐promoting effect and overexpression of prosaposin, may support a growth advantage to AI prostate cancer cells. Prostate © 2006 Wiley‐Liss, Inc.