Differential Peroxisome Proliferator-Activated Receptor-γ Isoform Expression and Agonist Effects in Normal and Malignant Prostate Cells

Peroxisome proliferator-activated receptor-γ (PPAR-γ) 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-γ than do normal prostate cells and are growth inhibited by ligand activation of PPAR-γ. 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)-γ1 and hPPAR-γ2 isoforms in normal prostate ECs to determine if activation of the receptor is sufficient for PPAR-γ ligand activity in prostate cells. We found that ECs did not express either PPAR-γ1 or PPAR-γ2 protein and were not sensitive to growth inhibition by the PPAR-γ ligand 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). In contrast, prostate cancer cells (PC-3), which express PPAR-γ1 receptor isoform, are growth inhibited by PPAR-γ ligand. Forced expression of hPPAR-γ1 or hPPAR-γ2 made ECs sensitive to 15d-PGJ2 and led to reduced cellular viability. The direct repeat-1 promoter containing PPAR response elements was transactivated in ECs expressing exogenous PPAR-γ1 or PPAR-γ2, 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-γ expression construct (either γ1 or γ2 isoform) into ECs. Addition of PPAR-γ ligand 15-hydroxyeicosatetraenoic acid in the presence of PPAR-γ expression caused further down-regulation of 15-lipoxygenase-2. Our data illustrate that a PPAR-γ ligand (15d-PGJ2) activates PPAR-γ1 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-γ-targeting agents that prevent or treat prostate cancer and spare normal prostate cells.