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15S-Hydroxyeicosatetraenoic Acid Activates Peroxisome Proliferator-activated Receptor and Inhibits Proliferation in PC3 Prostate Carcinoma Cells¹

Department of Pathology [S. B. S., S. M., J. P., G. S. J.], Vanderbilt Prostate Cancer Center [S. B. S., S. M., R. J. M.]; Vanderbilt-Ingram Cancer Center [S. B. S., R. W., R. J. M., A. R. B., R. N. D.]; Departments of Cell Biology [R. A. G., R. J. M., R. N. D.], Medicine, Division of Gastroenterology [R. A. G., R. W., R. N. D.], Pharmacology, Division of Clinical Pharmacology [W. E. B., C. S., A. R. B.], and Urology [T. C., R. J. M.], Vanderbilt University Medical Center, Nashville, Tennessee 37232; Department of Pathology and Laboratory Medicine, Veterans University Medical Center, Nashville, Tennessee 37212 [J. P.]; and Departments of Pathology and Urology, Baylor College of Medicine and The Methodist Hospital, Houston, Texas 77030 [T. M. W.]

15-Lipoxygenase (15-LOX)-2 is expressed in benign prostate secretory cells and benign prostate produces 15S-hydroxyeicosatetraenoic acid (15S-HETE) from exogenous arachidonic acid (AA). In contrast, 15S-LOX-2 and 15S-HETE formation are reduced in prostate carcinoma (Pca). The mechanisms whereby reduced 15-LOX-2 may contribute to Pca development or progression are not known. We investigated the expression of peroxisome proliferator-activated receptor (PPAR) in benign and malignant prostate tissues and the ability of 15S-HETE to activate PPAR-dependent transcription and modulate proliferation of the Pca cell line PC3. In contrast to benign prostate and similar to most Pca tissues, 15-LOX-2 mRNA was not detected in PC3 cells, and they did not produce detectable 15-HETE from [¹⁴C]AA. By reverse transcription-PCR, PPAR mRNA was present in 18 of 18 benign and 9 of 9 tumor specimens. The PPAR ligand BRL 49653 and 15S-HETE caused a dose-dependent inhibition of PC3 proliferation in a 14-day soft agar colony-forming assay (IC₅₀ of 3 and 30 µM, respectively). 15S-HETE (10 µM) caused greater inhibition than 10 µM 15R-HETE. At 3 days, BRL 49653 and 15S-HETE caused a slight increase in cells in G₀-G₁ and a corresponding decrease in cells in S phase. In PC3 cells transiently transfected with a luciferase reporter linked to a PPAR response element, 1 µM BRL 49653 and 10 µM 15S-HETE caused approximately threefold and greater than twofold induction of PPAR-dependent transcription, respectively. By quantitative real-time reverse transcription-PCR and Northern analysis, 3-day treatment with BRL 49653 and 15S-HETE caused a reduction of PPAR expression but a marked up-regulation of the PPAR response element containing adipocyte type fatty acid binding protein. These results support the hypothesis that 15-LOX-2-derived 15S-HETE may constitute an endogenous ligand for PPAR 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 carcinoma.

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