Prosaposin is an AR-target gene and its neurotrophic domain upregulates AR expression and activity in prostate stromal cells.
Recent studies have introduced prosaposin (PSAP) as a pleiotrophic growth factor for prostate cancer (PCa). We have previously reported that PSAP or one of its known active molecular derivatives, saposin C functions as an androgen-agonist and androgen-regulated gene (ARG) for androgen-sensitive (AS) PCa cell lines. Due to the potential significance of androgen receptor (AR)-expressing stroma in PCa, we evaluated a possible bi-directional paracrine regulatory interactions between DHT and PSAP in AR-positive prostate stromal (PrSt) cells. We report that saposin C in a ligand-independent manner increased AR expression, its nuclear content, and tyrosine phosphorylation. DHT treatment of PrSt cells increased PSAP expression. We also demonstrated both serum- and androgen-inducibility of a previously characterized hormone-responsive element (HRE) located in the proximal region of PSAP promoter. In addition, conditioned-media derived from PrSt cells and bone fibroblasts (i.e., MSF) differentially increased PSAP-promoter activity in androgen-independent (AI) PC-3 and AS LNCaP cells. Our data for the first time demonstrate that not only saposin C or PSAP regulates AR expression/activity, but also function as an ARG in PrSt. Ligand-independent activation of AR by PSAP or saposin C in PCa and stromal cells may contribute not only to prostate carcinogenesis at an early stage, but also in AI progression of the disease in an androgen-deprived tumor microenvironment.
Koochekpour
S
S
Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA. skooch@lsuhsc.edu
Lee
T-J
TJ
Sun
Y
Y
Hu
S
S
Grabowski
G A
GA
Liu
Z
Z
Garay
J
J
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D001842:Bone and Bones / Q000166:cytology; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned; D013196:Dihydrotestosterone / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000737:chemistry*; D019000:Phosphotyrosine / Q000378:metabolism; D011467:Prostate / Q000166:cytology*; D011471:Prostatic Neoplasms / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D049231:Saposins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D044967:Serum; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
C410798:AR protein, human; D000728:Androgens; D017077:Culture Media, Conditioned; D009414:Nerve Growth Factors; C483345:PSAP protein, human; D011944:Receptors, Androgen; D049231:Saposins; D013196:Dihydrotestosterone; D019000:Phosphotyrosine