15-Lipoxygenase-2 gene regulation by its product 15-(S)-hydroxyeicosatetraenoic acid through a negative feedback mechanism that involves peroxisome proliferator-activated receptor gamma

Oncogene. 2006 Sep 28;25(44):6015-25. doi: 10.1038/sj.onc.1209617. Epub 2006 May 8.


An inverse relationship exists between the expression of 15-lipoxygenase-2 (15-LOX-2) and peroxisome proliferator-activated receptor gamma (PPARgamma) in normal prostate epithelial cells (PrECs) compared with their expression in prostate carcinoma cells (PC-3). The reason for this difference, however, is unknown. We hypothesized that this inverse expression partly involves the 15-LOX-2 promoter and 15-S-hydroxyeicosatetraenoic acid (15-(S)-HETE), a product of 15-LOX-2 that binds to PPARgamma. We identified an active steroid nuclear receptor half-site present in the 15-LOX-2 promoter fragment F-5 (-618/+177) that can interact with PPARgamma. After forced expression of wild-type PPARgamma, 15-(S)-HETE (1 microM) decreased F-5 reporter activity in PrECs whereas forced expression of 15-LOX-2 resulted in 15-(S)-HETE production which enhanced F-5 activity in PC-3. In contrast, the expression of dominant-negative PPARgamma reversed the transcriptional activation of F-5 by enhancing it 202-fold in PrEC or suppressing it in PC-3; the effect in PC-3 was positively increased 150-fold in the presence of 15-(S)-HETE (1 microM). Peroxisome proliferator-activated receptor gamma interacted with 15-LOX-2 promoter sequences in pulldown experiments using biotinylated 15-LOX-2 (-560/-596 bp) oligonucleotides. In gelshift analyses PPARgamma and orphan receptor RORalpha were shown to interact with the F-5 fragment in PC-3 cells. These data suggest that crosstalk mechanisms exist between the 15-LOX-2 gene and PPARgamma to counterbalance expression and help explain the inverse relationship of these genes in normal versus cancer cells.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions
  • Arachidonate 15-Lipoxygenase / biosynthesis*
  • Arachidonate 15-Lipoxygenase / genetics*
  • Cell Line
  • Cell Line, Tumor
  • Chromosomes, Human, Pair 17 / enzymology
  • Chromosomes, Human, Pair 17 / genetics
  • Cloning, Molecular
  • Down-Regulation / genetics*
  • Enhancer Elements, Genetic
  • Feedback, Physiological / genetics*
  • Humans
  • Hydroxyeicosatetraenoic Acids / physiology*
  • Lipoxygenase Inhibitors
  • Male
  • PPAR gamma / physiology*
  • Promoter Regions, Genetic
  • Prostate / cytology
  • Prostate / enzymology
  • Prostate / metabolism
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Receptor Cross-Talk / physiology
  • Up-Regulation / genetics


  • 5' Untranslated Regions
  • Hydroxyeicosatetraenoic Acids
  • Lipoxygenase Inhibitors
  • PPAR gamma
  • 15-hydroxy-5,8,11,13-eicosatetraenoic acid
  • Arachidonate 15-Lipoxygenase