Subbarayan Vemparala, Sabichi Anita L, Kim Jeri, Llansa Norma, Logothetis Christopher J, Lippman Scott M, Menter David G
Department of Clinical Cancer Prevention, University of Texas M.D. Anderson Cancer Center, Unit 236, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cancer Epidemiol Biomarkers Prev. 2004 Nov;13(11 Pt 1):1710-6.
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.
过氧化物酶体增殖物激活受体γ（PPAR-γ）因其在致癌作用以及介导前列腺癌治疗和预防药物的作用方面而受到深入研究。前列腺癌中PPAR-γ的组成性表达水平比正常前列腺细胞丰富且更高，并且通过PPAR-γ的配体激活可抑制其生长。然而，关于PPAR在肿瘤发生或正常前列腺上皮细胞（EC）中的作用知之甚少。我们检测了人PPAR（hPPAR）-γ1和hPPAR-γ2亚型在正常前列腺EC中的表达、磷酸化模式和功能，以确定受体的激活是否足以产生前列腺细胞中PPAR-γ配体的活性。我们发现EC既不表达PPAR-γ1也不表达PPAR-γ2蛋白，并且对PPAR-γ配体15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2）的生长抑制不敏感。相比之下，表达PPAR-γ1受体亚型的前列腺癌细胞（PC-3）受到PPAR-γ配体的生长抑制。hPPAR-γ1或hPPAR-γ2的强制表达使EC对15d-PGJ2敏感并导致细胞活力降低。含有PPAR反应元件的直接重复序列-1启动子在表达外源性PPAR-γ1或PPAR-γ2的EC中被反式激活，表明任一亚型在这些细胞中均可具有活性。在EC中高水平表达的15-脂氧合酶-2通过将PPAR-γ表达构建体（γ1或γ2亚型）转染到EC中而下调。在存在PPAR-γ表达时添加PPAR-γ配体15-羟基二十碳四烯酸导致15-脂氧合酶-2进一步下调。我们的数据表明，PPAR-γ配体（15d-PGJ2）激活PPAR-γ1并选择性诱导人前列腺癌细胞而非正常前列腺EC中的细胞死亡。这些发现对于开发预防或治疗前列腺癌并使正常前列腺细胞免受影响的PPAR-γ靶向药物具有重要意义。
