Colon Cancer Research Today is a free monthly online journal that collates and summarizes the latest research about Colon Cancer, including details on causes, treatment, symptoms. | ||||||||
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Synergistic effects of RXR alpha and PPAR gamma ligands to inhibit growth in human colon cancer cells--phosphorylated RXR alpha is a critical target for colon cancer management.Yamazaki K, Shimizu M, Okuno M, Matsushima-Nishiwaki R, Kanemura N, Araki H, Tsurumi H, Kojima S, Weinstein IB, Moriwaki H Department of Medicine, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. BACKGROUND AND AIMS: The activation of the peroxisome proliferator-activated receptor gamma (PPAR gamma) that forms heterodimers with retinoid X receptors (RXRs) elicits an antineoplastic effect on colorectal cancer. It was previously reported that the accumulation of the non-functional phosphorylated form of RXR alpha (p-RXR alpha) interfered with its signalling and promoted the growth of hepatoma cells. In this study the effects of p-RXR alpha on the ability of RXR alpha and PPAR gamma ligands to inhibit growth in colon cancer cells was examined. METHODS: The effects of the combination of the PPAR gamma ligand ciglitazone and the RXR alpha lignad 9-cis-retinoic acid (RA) on inhibition of cell growth in Caco2 human colon cancer cells which express high levels of p-RXR alpha protein were examined. RESULTS: The RXR alpha protein was phospholylated and also accumulated in human colon cancer tissue samples as well as human colon cancer cell lines. When the phosphorylation of RXR alpha was inhibited by the MEK inhibitor PD98059 or by transfection with a point-mutated RXR alpha, which mimicked the unphosphorylated form, the combination of 9-cisRA and ciglitazone synergistically inhibited the cell growth and induced apoptosis. The combined treatment with these agents also caused a decrease in the expression levels of both cyclo-oxygenase-2 (COX-2) and c-Jun proteins and mRNAs. Reporter assays indicated that this combination induced the transcriptional activity of the peroxisome proliferator-responsive element promoter and also inhibited that of the AP-1 promoter. CONCLUSION: A malfunction of RXR alpha due to phosphorylation is associated with colorectal cancer. Therefore, the inhibition of phosphorylation of RX R alpha and the activation of the RXR-PPAR gamma heterodimer by their respective ligands may be useful in the chemoprevention and/or treatment of colorectal cancer. Published 16 October 2007 in Gut, 56(11): 1557-63.
© 2004-2008 Colon Cancer Research Today. All Rights Reserved. |
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