Differential peroxisome proliferator-activated receptor-gamma isoform expression and agonist effects in normal and malignant prostate cells.
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.
Subbarayan
Vemparala
V
Department of Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Unit 236, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Sabichi
Anita L
AL
Kim
Jeri
J
Llansa
Norma
N
Logothetis
Christopher J
CJ
Lippman
Scott M
SM
Menter
David G
DG
D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D016923:Cell Death; D002478:Cells, Cultured; D006801:Humans; D049409:Luciferases, Firefly / Q000494:pharmacology; D049408:Luminescent Agents / Q000494:pharmacology; D008297:Male; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D020033:Protein Isoforms; D015533:Transcriptional Activation / Q000187:drug effects
C477819:15-deoxyprostaglandin J2; D049408:Luminescent Agents; D047495:PPAR gamma; D020033:Protein Isoforms; D049409:Luciferases, Firefly; D015230:Prostaglandin D2