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

Departments of ¹ Clinical Cancer Prevention and ² Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: David G. Menter, Department of Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Unit 236, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-0626; Fax: 713-794-4403. E-mail: dmenter{at}mdanderson.org

Peroxisome proliferator-activated receptor- (PPAR-) 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- than do normal prostate cells and are growth inhibited by ligand activation of PPAR-. 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)-1 and hPPAR-2 isoforms in normal prostate ECs to determine if activation of the receptor is sufficient for PPAR- ligand activity in prostate cells. We found that ECs did not express either PPAR-1 or PPAR-2 protein and were not sensitive to growth inhibition by the PPAR- ligand 15-deoxy-12,14-prostaglandin J₂ (15d-PGJ₂). In contrast, prostate cancer cells (PC-3), which express PPAR-1 receptor isoform, are growth inhibited by PPAR- ligand. Forced expression of hPPAR-1 or hPPAR-2 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-1 or PPAR-2, 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- expression construct (either 1 or 2 isoform) into ECs. Addition of PPAR- ligand 15-hydroxyeicosatetraenoic acid in the presence of PPAR- expression caused further down-regulation of 15-lipoxygenase-2. Our data illustrate that a PPAR- ligand (15d-PGJ₂) activates PPAR-1 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--targeting agents that prevent or treat prostate cancer and spare normal prostate cells.

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