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Peroxisome Proliferator-activated Receptor Is an Androgen-responsive Gene in Human Prostate and Is Highly Expressed in Prostatic Adenocarcinoma¹

School of Surgical and Reproductive Sciences, University of Newcastle upon Tyne, Newcastle NE2 4HH, United Kingdom

Peroxisome proliferator-activated receptor (PPAR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPAR 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 PPAR-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 PPAR mRNA. Levels of PPAR mRNA are reduced to approximately 40% of control levels in LNCaP cells exposed to 10 nM mibolerone for 96 h. PPAR-responsive reporter plasmids derived from human ApoA-II and muscle carnitine palmitoyl-transferase I genes were stimulated by the PPAR-activating ligand Wy-14,643 in LNCaP cells. In situ hybridization and immunohistochemical analyses showed that PPAR expression in prostate is confined to epithelial cells. In benign prostatic tissue, PPAR 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 PPAR 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 PPAR is found and functional in human prostate and is down-regulated by androgens. The role of PPAR 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.

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