15-deoxyprostaglandin-j2 and Prostatic-Neoplasms

Androgen signaling, in particular overexpression of the androgen receptor (AR), is critical for the growth and progression of prostate cancer. Because the AR is amenable to targeting by small-molecule inhibitors, it remains the major druggable target for the advanced disease. Inflammation has also been implicated in the cancerous growth in the prostate. Here we show that 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), an endogenously produced antiinflammatory prostaglandin, targets the AR and acts as a potent AR inhibitor, rapidly repressing AR target genes, such as FKBP51 and TMPRSS2 in prostate cancer cells. However, exposure of prostate cancer cells to 15d-PGJ(2) does not simply evoke a general inhibition of nuclear receptor activity or transcription because under the same conditions, peroxisome proliferator-activated receptor-γ is activated by 15d-PGJ(2). Moreover, 15d-PGJ(2) rapidly triggers modifications of AR by small ubiquitin-related modifier-2/3 (SUMO-2/3), which may modulate the repressing effect of 15d-PGJ(2) on AR-dependent transcription. Chromatin immunoprecipitation assays indicate that the inhibitory effect of 15d-PGJ(2) on FKBP51 and TMPRSS2 expression occurs in parallel with the inhibition of the AR binding to the regulatory regions of these genes. However, the DNA-binding activity is not the only AR function targeted by 15d-PGJ(2) because the prostaglandin also blunted the androgen-dependent interaction between the AR amino and carboxy termini. In conclusion, our results identify 15d-PGJ(2) as a potent and direct inhibitor of androgen signaling, suggesting novel possibilities in restricting the AR activity in prostate cancer cells.

Topics: Androgen Receptor Antagonists; Animals; Cell Line, Tumor; Chlorocebus aethiops; Chromatin Immunoprecipitation; COS Cells; Electrophoretic Mobility Shift Assay; Genes, Reporter; Humans; Male; PPAR gamma; Prostaglandin D2; Prostatic Neoplasms; Protein Binding; Receptors, Androgen; Serine Endopeptidases; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Sumoylation; Tacrolimus Binding Proteins; Transcription Factors; Transcription, Genetic; Ubiquitins

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is expressed in certain human cancers. Ligand-induced PPAR-gamma activation can result in growth inhibition and differentiation in these cancer cells; however, the precise mechanism for the anti-proliferative effect of PPAR-gamma ligands is not clear.. In this study, we examined the expression of PPAR-gamma in human prostate cancer and the effect of two PPAR-gamma ligands, 15 deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) and troglitazone, on prostate cancer cell growth.. PPAR-gamma is frequently over-expressed in androgen independent prostate cancer cell lines and human prostate cancer tissues (22 of 47; 47%). Both 15d-PGJ2 and troglitazone inhibited proliferation and DNA synthesis of prostate cancer cell lines in a dose-dependent manner, and slightly increased the proportion of cells with S-phase DNA content. Prostate specific antigen (PSA) promoter reporter assays showed that troglitazone and 15d-PGJ2 down-regulated androgen stimulated reporter gene activity in prostate cancer cell lines LNCaP. Interestingly, LNCaP with troglitazone dramatically suppressed PSA protein expression without suppressing AR expression.. Taken together, these results suggest that PPAR-gamma ligands may be a useful therapeutic agent for the treatment of prostate cancer.

Topics: Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Chromans; Flow Cytometry; Humans; Immunohistochemistry; Ligands; Male; PPAR gamma; Promoter Regions, Genetic; Prostaglandin D2; Prostate-Specific Antigen; Prostatic Neoplasms; Receptors, Androgen; Thiazolidinediones; Transfection; Troglitazone

Although PPARgamma antagonists have shown considerable pre-clinical efficacy, recent studies suggest PPARgamma ligands induce PPARgamma-independent effects. There is a need to better define such effects to permit rational utilization of these agents.. We have studied the effects of a range of endogenous and synthetic PPARgamma ligands on proliferation, growth arrest (FACS analysis) and apoptosis (caspase-3/7 activation and DNA fragmentation) in multiple prostate carcinoma cell lines (DU145, PC-3 and LNCaP) and in a series of cell lines modelling metastatic transitional cell carcinoma of the bladder (TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2).. 15-deoxy-prostaglandin J2 (15dPGJ2), troglitazone (TGZ) and to a lesser extent ciglitazone exhibited inhibitory effects on cell number; the selective PPARgamma antagonist GW9662 did not reverse these effects. Rosiglitazone and pioglitazone had no effect on proliferation. In addition, TGZ induced G0/G1 growth arrest whilst 15dPGJ2 induced apoptosis.. Troglitazone and 15dPGJ2 inhibit growth of prostate and bladder carcinoma cell lines through different mechanisms and the effects of both agents are PPARgamma-independent.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma; Carcinoma, Transitional Cell; Caspase 3; Caspase 7; Caspases; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Chromans; DNA Fragmentation; Humans; Ligands; Male; PPAR gamma; Prostaglandin D2; Prostatic Neoplasms; RNA, Messenger; Thiazolidinediones; Troglitazone; Urinary Bladder Neoplasms

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.

Topics: Animals; Blotting, Western; Cattle; Cell Death; Cells, Cultured; Humans; Luciferases, Firefly; Luminescent Agents; Male; Phosphorylation; PPAR gamma; Prostaglandin D2; Prostate; Prostatic Neoplasms; Protein Isoforms; Transcriptional Activation