Peroxisome proliferator-activated receptor α is an androgen-responsive gene in human prostate and is highly expressed in prostatic adenocarcinoma

Peroxisome proliferator-activated receptor (PPAR) α is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARα is activated by peroxisome proliferators and fatty acids and has been shown to be involved in the transcriptional regulation of genes involved in fatty acid metabolism. In rodents, the PPARα-mediated change in such 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 results in the down-regulation of PPARα mRNA. Levels of PPARα mRNA are reduced to approximately 40% of control levels in LNCaP cells exposed to 10 nM mibolerone for 96 h. PPARα-responsive reporter plasmids derived from human ApoA-II and muscle carnitine palmitoyl-transferase I genes were stimulated by the PPARα-activating ligand Wy-14,643 in LNCaP cells. In situ hybridization and immunohistochemical analyses showed that PPARα expression in prostate is confined to epithelial cells. In benign prostatic tissue, PPARα mRNA was either absent or only weakly expressed in the basal epithelial cells. In 11 of 18 (61%) poorly differentiated (Gleason score, 8-10) prostatic carcinoma specimens, there was strong expression of PPARα compared with 4 of 12 Gleason score 7 tumors and 2 of 11 Gleason score 3-6 tumors (P < 0.01). These results suggest that PPARα is found and functional in human prostate and is down-regulated by androgens. The role of PPARα may be to integrate dietary fatty acid and steroid hormone signaling pathways, and its overexpression in advanced prostate cancer may indicate a role in tumor progression with the potential involvement of dietary factors.