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

Scott B. Shappell, Rajnish A. Gupta, Suzanne Manning, Robert Whitehead, William E. Boeglin, Claus Schneider, Tom Case, James Price, Gregory S. Jack, Thomas M. Wheeler, Robert J. Matusik, Alan R. Brash, Raymond N. DuBois

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193 Scopus citations

Abstract

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) γ in benign and malignant prostate tissues and the ability of 15S-HETE to activate PPARγ-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, PPARγ mRNA was present in 18 of 18 benign and 9 of 9 tumor specimens. The PPARγ ligand BRL 49653 and 15S-HETE caused a dose-dependent inhibition of PC3 proliferation in a 14-day soft agar colony-forming assay (IC50of 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-G1and 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 PPARγ 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 PPARγ 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.

Original languageEnglish (US)
Pages (from-to)497-503
Number of pages7
JournalCancer Research
Volume61
Issue number2
StatePublished - Jan 15 2001

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Shappell, S. B., Gupta, R. A., Manning, S., Whitehead, R., Boeglin, W. E., Schneider, C., Case, T., Price, J., Jack, G. S., Wheeler, T. M., Matusik, R. J., Brash, A. R., & DuBois, R. N. (2001). 15S-hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor γ and inhibits proliferation in PC3 prostate carcinoma cells. Cancer Research, 61(2), 497-503.