Search

Background: Evidence of the chemopreventive effects of the dietary antioxidants α-tocopherol (vitamin E) and l-selenomethionine (selenium) comes from secondary analysis of two phase III clinical trials that found treatment with these antioxidants reduced the incidence of prostate cancer. To determine the effects of selenium and vitamin E in blood and prostate tissue, we undertook a preoperative feasibility study complementary to the currently ongoing Selenium and Vitamin E Cancer Prevention Trial.Methods: Forty-eight patients with clinically localized prostate cancer enrolled on this 2 × 2 factorial design study were randomized to take selenium, vitamin E, both, or placebo for 3 to 6 weeks before prostatectomy. Sera were collected from patients before and after dietary supplementation. Thirty-nine patients were evaluable, and 29 age-matched disease-free men served as controls. Mass profiling of lipophilic serum proteins of lower molecular weight (2-13.5 kDa) was conducted, and mass spectra data were analyzed using custom-designed software.Results: Weighted voting analyses showed a change in sera classification from cancerous to healthy for some patients with prostate cancer after dietary intervention. ANOVA analysis showed significantly different treatment effects on prediction strength changes among the four groups at a 95% confidence level. Eliminating an outlying value and performing post hoc analysis using Fisher's least significant difference method showed that effects in the group treated with the combination were significantly different from those of the other groups.Conclusion: In sera from patients with prostate cancer, selenium and vitamin E combined induced statistically significant proteomic pattern changes associated with prostate cancer–free status.

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.

Recent studies have found that cyclooxygenase-2 (COX-2) protein expression was low and inducible with cytokines in prostate cancer cells (in the absence of serum) and that, in contrast, COX-2 expression was high in normal prostate epithelial cells (EC). Peroxisome proliferator-activated receptor-γ (PPAR-γ) was expressed at high levels in the prostate cancer cell line PC-3 but not in ECs. In contrast to previous findings by others, PPAR-γ ligands did not induce PPAR-γ expression in EC or PC-3. The present study examined the relationship between PPAR-γ and COX-2 expression patterns in EC and PC-3 in the presence and absence of serum and/or the PPAR-γ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). We also evaluated the effects that the forced expression of PPAR-γ1 and PPAR-γ2 had on COX-2 in ECs. We found that expression of PPAR-γ and COX-2 protein was inversely correlated in ECs and PC-3. Low COX-2 expression in PC-3 was up-regulated by serum, and 15d-PGJ2 blocked serum-induced COX-2 expression and activity in a dose-dependent manner. 15d-PGJ2 had no effect on COX-2 expression in ECs or PPAR-γ expression in either cell type. However, forced expression of PPAR-γ1 or PPAR-γ2 in ECs suppressed the high level of endogenous COX-2. This effect was not isoform specific and was augmented by 15d-PGJ2. The present study showed that PPAR-γ activation can be an important regulator of COX-2 in prostate cells and may be an important target for prostate cancer chemoprevention.