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Synergistic Effects of RXRα and PPARγ Ligands to Inhibit Growth in Human Colon Cancer Cells - Phosphorylated RXRα is a Critical Target for Colon Cancer Management 1
  1. Kenji Yamazaki
  1. Department of Medicine, Gifu University School of Medicine, Japan
    1. Masahito Shimizu (shimim-gif{at}umin.ac.jp)
    1. Department of Medicine, Gifu University School of Medicine, Japan
      1. Masataka Okuno
      1. Department of Medicine, Gifu University School of Medicine, Japan
        1. Rie Matsushima-Nishiwaki
        1. Department of Medicine, Gifu University School of Medicine, Japan
          1. Nobuhiro Kanemura
          1. Department of Medicine, Gifu University School of Medicine, Japan
            1. Hiroshi Araki
            1. Department of Medicine, Gifu University School of Medicine, Japan
              1. Hisashi Tsurumi
              1. Department of Medicine, Gifu University School of Medicine, Japan
                1. Soichi Kojima
                1. Molecular Cellular Pathology Research Unit, Discovery Research Institute, Riken, Japan
                  1. I Bernard Weinstein
                  1. Columbia University Medical Center, United States
                    1. Hisataka Moriwaki
                    1. Department of Medicine, Gifu University School of Medicine, Japan

                      Abstract

                      Background & Aims: The activation of PPARγ that forms heterodimers with RXRs elicits an antineoplastic effect on colorectal cancer. We previously reported that the accumulation of non-functional phosphorylated form of RXRα (p-RXRαinterfered with its signaling and promoted the growth of hepatoma cells. In this study we examined the effects of p-RXRα on the ability of RXRα and PPARγ ligands to inhibit growth in colon cancer cells.

                      Methods: We examined the effects of the combination of the PPARγ ligand ciglitazone and the RXRα lignad 9-cisRA on inhibition of cell growth in Caco2 human colon cancer cells which express high levels of p-RXRα protein.

                      Results: The RXRα protein was phospholylated and also accumulated in human colon cancer tissue samples as well as human colon cancer cell lines. When the phosphorylation of RXRα was inhibited by the MEK inhibitor PD98059 or by transfection with a point-mutated RXRα, 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 COX-2 and c-Jun proteins and mRNAs. Reporter assays indicated that this combination induced the transcriptional activity of the PPRE promoter and also inhibited that of AP-1 promoter.

                      Conclusion: A malfunction of RXRα due to phosphorylation is associated with colorectal cancer. Therefore, the inhibition of phosphorylation of RXRα and the activation of the RXR/PPARγ heterodimer by their respective ligands may be useful in the chemoprevention and/or treatment of colorectal cancer.

                      • COX-2
                      • ciglitazone
                      • colorectal cancer
                      • RXRα
                      • retinoic acid

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