Differential peroxisome proliferator-activated receptor-gamma isoform expression and agonist effects in normal and malignant prostate cells

Cancer Epidemiol Biomarkers Prev. 2004 Nov;13(11 Pt 1):1710-6.


Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is being studied intensively for its role in carcinogenesis and in mediating the effects of prostate cancer treatment and prevention drugs. Prostate cancers express abundant and higher constitutive levels of PPAR-gamma than do normal prostate cells and are growth inhibited by ligand activation of PPAR-gamma. However, little is known about the role of PPARs in tumorigenesis or in normal prostate epithelial cells (EC). We examined the expression, phosphorylation patterns, and functions of the human PPAR (hPPAR)-gamma1 and hPPAR-gamma2 isoforms in normal prostate ECs to determine if activation of the receptor is sufficient for PPAR-gamma ligand activity in prostate cells. We found that ECs did not express either PPAR-gamma1 or PPAR-gamma2 protein and were not sensitive to growth inhibition by the PPAR-gamma ligand 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)). In contrast, prostate cancer cells (PC-3), which express PPAR-gamma1 receptor isoform, are growth inhibited by PPAR-gamma ligand. Forced expression of hPPAR-gamma1 or hPPAR-gamma2 made ECs sensitive to 15d-PGJ(2) and led to reduced cellular viability. The direct repeat-1 promoter containing PPAR response elements was transactivated in ECs expressing exogenous PPAR-gamma1 or PPAR-gamma2, indicating that either isoform can be active in these cells. 15-Lipoxygenase-2, expressed at high levels in ECs, was down-regulated by transfecting PPAR-gamma expression construct (either gamma1 or gamma2 isoform) into ECs. Addition of PPAR-gamma ligand 15-hydroxyeicosatetraenoic acid in the presence of PPAR-gamma expression caused further down-regulation of 15-lipoxygenase-2. Our data illustrate that a PPAR-gamma ligand (15d-PGJ(2)) activates PPAR-gamma1 and selectively induces cell death in human prostate cancer cells but not in normal prostate ECs. These findings have important implications for the development of PPAR-gamma-targeting agents that prevent or treat prostate cancer and spare normal prostate cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Cattle
  • Cell Death
  • Cells, Cultured
  • Humans
  • Luciferases, Firefly / pharmacology
  • Luminescent Agents / pharmacology
  • Male
  • PPAR gamma / agonists
  • PPAR gamma / genetics*
  • PPAR gamma / metabolism
  • PPAR gamma / physiology
  • Phosphorylation / drug effects
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / pharmacology*
  • Prostaglandin D2 / therapeutic use
  • Prostate / drug effects*
  • Prostate / metabolism
  • Prostatic Neoplasms / etiology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / prevention & control
  • Protein Isoforms
  • Transcriptional Activation / drug effects


  • 15-deoxyprostaglandin J2
  • Luminescent Agents
  • PPAR gamma
  • Protein Isoforms
  • Luciferases, Firefly
  • Prostaglandin D2