James Sharon Y, Lin Feng, Kolluri Siva Kumar, Dawson Marcia I, Zhang Xiao-kun
Cancer Center, The Burnham Institute, La Jolla, California 92037, USA.
Cancer Res. 2003 Jul 1;63(13):3531-8.
The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor family member that can form a heterodimeric complex with retinoid X receptor (RXR) and initiate transcription of target genes. In this study, we have examined the effects of the PPAR gamma ligand ciglitazone and the RXR ligand SR11237 on growth and induction of retinoic acid receptor (RAR) beta expression in breast and lung cancer cells. Our results demonstrated that ciglitazone and SR11237 cooperatively inhibited the growth of ZR-75-1 and T-47D breast cancer and Calu-6 lung cancer cells. Gel shift analysis indicated that PPAR gamma, in the presence of RXR, formed a strong complex with a retinoic acid response element (beta retinoic acid response element) in the RAR beta promoter. In reporter gene assays, RXR ligands and ciglitazone, but not the PPAR gamma ligand 15d-PGJ(2), cooperatively promoted the transcriptional activity of the beta retinoic acid response element. Ciglitazone, but not 15d-PGJ(2), strongly induced RAR beta expression in human breast and lung cancer cell lines when used together with SR11237. The induction of RAR beta expression by the ciglitazone and SR11237 combination was diminished by a PPAR gamma-selective antagonist, bisphenol A diglycidyl ether. All-trans-retinoic acid or the combination of ciglitazone and SR11237 was able to induce RAR beta in all-trans-retinoic acid-resistant MDA-MB-231 breast cancer cells only when the orphan receptor chick ovalbumin upstream promoter transcription factor was expressed, or in the presence of the histone deacetylase inhibitor trichostatin A. These studies indicate the existence of a novel RAR beta-mediated signaling pathway of PPAR gamma action, which may provide a molecular basis for developing novel therapies involving RXR and PPAR gamma ligands in potentiating antitumor responses.
过氧化物酶体增殖物激活受体γ（PPARγ）是核受体家族成员，可与视黄酸X受体（RXR）形成异二聚体复合物并启动靶基因转录。在本研究中，我们检测了PPARγ配体环格列酮和RXR配体SR11237对乳腺癌和肺癌细胞生长及维甲酸受体（RAR）β表达诱导的影响。我们的结果表明，环格列酮和SR11237协同抑制ZR-75-1和T-47D乳腺癌细胞以及Calu-6肺癌细胞的生长。凝胶迁移分析表明，PPARγ在RXR存在的情况下，与RARβ启动子中的视黄酸反应元件（β视黄酸反应元件）形成强复合物。在报告基因分析中，RXR配体和环格列酮，而非PPARγ配体15d-PGJ2，协同促进β视黄酸反应元件的转录活性。当与SR11237联合使用时，环格列酮而非15d-PGJ2强烈诱导人乳腺癌和肺癌细胞系中RARβ的表达。PPARγ选择性拮抗剂双酚A二缩水甘油醚可减弱环格列酮和SR11237联合诱导的RARβ表达。仅当孤儿受体鸡卵清蛋白上游启动子转录因子表达时，或在组蛋白去乙酰化酶抑制剂曲古抑菌素A存在的情况下，全反式维甲酸或环格列酮与SR11237的组合才能在全反式维甲酸耐药的MDA-MB-231乳腺癌细胞中诱导RARβ。这些研究表明存在一种新的PPARγ作用的RARβ介导的信号通路，这可能为开发涉及RXR和PPARγ配体增强抗肿瘤反应的新疗法提供分子基础。
