15S-hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells

15-lipoxygenase: (15-LOX)-2 is expressed in benign prostate secretory cells and benign prostate produces 15S-hydroxyeicosatetraenoic acid (15S-HETE) f rom exogenous arachidonic acid (AA), In contrast, 15S-LOX-2 and ISS-HETE fo rmation are reduced in prostate carcinoma (Pca). The mechanisms whereby red uced 15-LOX-2 may contribute to Pea development or progression are not know n, We investigated the expression of peroxisome proliferator-activated rece ptor (PPAR) gamma in benign and malignant prostate tissues and the ability of LSS-HETE to activate PPAR gamma -dependent transcription and modulate pr oliferation of the Pea cell line PC3. In contrast to benign prostate and si milar to most Pea tissues, 15-LOX-2 mRNA was not detected in PC3 cells, and they did not produce detectable 15-HETE from [C-14]AA. By reverse transcri ption-PCR, PPAR gamma mRNA was present in 18 of 18 benign and 9 of 9 tumor specimens. The PPAR gamma ligand BRL 49653 and 15S-HETE caused a dose-depen dent inhibition of PC3 proliferation in a 14-day soft agar colony-forming a ssay (IC50 of 3 and 30 muM, respectively). 15S-HETE (10 muM) caused greater inhibition than 10 muM 15R-HETE. At 3 days, BRL 49653 and ISS-HETE caused a slight increase in cells in G(0)-G(1) and a corresponding decrease in cel ls in S phase. In PC3 cells transiently transfected with a luciferase repor ter linked to a PPAR response element, 1 muM BRL 49653 and 10 muM 15S-HETE caused approximately threefold and greater than twofold induction of PPAR-d ependent transcription, respectively, By quantitative real-time reverse tra nscription-PCR and Northern analysis, 3-day treatment with BRL 49653 and 15 S-HETE caused a reduction of PPAR gamma expression but a marked up-regulati on of the PPAR response element containing adipocyte type fatty acid bindin g protein. These results support the hypothesis that 15-LOX-2-derived 15S-H ETE may constitute an endogenous ligand for PPAR gamma in the prostate and that loss of this pathway by reduced expression of 15-LOX-2 may contribute to increased proliferation and reduced differentiation in prostate carcinom a.