Peroxisome proliferator-activated receptor alpha is an androgen-responsivegene in human prostate and is highly expressed in prostatic adenocarcinoma

Peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPA R alpha is activated by peroxisome proliferators and fatty acids and has be en shown to be involved in the transcriptional regulation of genes involved in fatty acid metabolism, In rodents, the PPAR alpha-mediated change in su ch genes results in peroxisome proliferation and can lead to the induction of hepatocarcinogenesis, Using the mRNA differential display technique and Northern blot analysis, we have shown that chronic exposure of the prostate cancer epithelial cell line LNCaP to the synthetic androgen mibolerone res ults in the down-regulation of PPAR alpha mRNA, Levels of PPAR alpha mRNA a re reduced to approximately 40% of control levels in LNCaP cells exposed to 10 nM mibolerone for 96 h, PPAR alpha-responsive reporter plasmids derived from human ApoA-II and muscle carnitine palmitoyl-transferase I genes were stimulated by the PPAR(v.-activating ligand Wy-14,643 in LNCaP cells. In s itu hybridization and immunohistochemical analyses showed that PPAR alpha e xpression in prostate is confined to epithelial cells, In benign prostatic tissue, PPAR alpha. mRNA was either absent or only weakly expressed in the basal epithelial cells. In 11 of 18 (61%) poorly differentiated (Gleason sc ore, 8-10) prostatic carcinoma specimens, there was strong expression of PP AR alpha compared with 4 of 12 Gleason score 7 tumors and 2 of 11 Gleason s core 3-6 tumors (P < 0.01), These results suggest that PPAR alpha is found and functional in human prostate and is down-regulated by androgens, The ro le of PPARa may be to integrate dietary fatty acid and steroid hormone sign aling pathways, and its overexpression in advanced prostate cancer may indi cate a role in tumor progression with the potential involvement of dietary factors.