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[Cancer Research 63, 3531-3538, July 1, 2003]
© 2003 American Association for Cancer Research

Carcinogenesis

Regulation of Retinoic Acid Receptor ß Expression by Peroxisome Proliferator-activated Receptor {gamma} Ligands in Cancer Cells1

Sharon Y. James, Feng Lin, Siva Kumar Kolluri, Marcia I. Dawson and Xiao-kun Zhang2

Cancer Center, The Burnham Institute, La Jolla, California 92037

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) ß 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 (ß retinoic acid response element) in the RARß promoter. In reporter gene assays, RXR ligands and ciglitazone, but not the PPAR{gamma} ligand 15d-PGJ2, cooperatively promoted the transcriptional activity of the ß retinoic acid response element. Ciglitazone, but not 15d-PGJ2, strongly induced RARß expression in human breast and lung cancer cell lines when used together with SR11237. The induction of RARß 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 RARß 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 RARß-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.




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Copyright © 2003 by the American Association for Cancer Research.