Inhibition of Peroxisome Proliferator-Activated Receptor .GAMMA. Promotes Tumorigenesis Through Activation of the .BETA.-Catenin / T Cell Factor (TCF) Pathway in the Mouse Intestine

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Author(s)

    • Fujisawa Toshio
    • Division of Gastroenterology, Yokohama City University School of Medicine, Japan
    • Saito Satoru
    • Division of Gastroenterology, Yokohama City University School of Medicine, Japan
    • Terauchi Yasuo
    • Division of Endocrinology and Metabolism, Yokohama City University School of Medicine, Japan
    • Kadowaki Takashi
    • Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Japan
    • Tsuchiya Naoto
    • Biochemistry Division, National Cancer Center Research Institute, Japan
    • Nakagama Hitoshi
    • Biochemistry Division, National Cancer Center Research Institute, Japan
    • Nakajima Atsushi
    • Division of Gastroenterology, Yokohama City University School of Medicine, Japan
    • Sugiyama Michiko
    • Division of Gastroenterology, Yokohama City University School of Medicine, Japan
    • Tomimoto Ayako
    • Division of Gastroenterology, Yokohama City University School of Medicine, Japan
    • Wada Koichiro
    • Department of Pharmacology, Graduate School of Dentistry, Osaka University, Japan
    • Endo Hiroki
    • Division of Gastroenterology, Yokohama City University School of Medicine, Japan
    • Takahashi Hirokazu
    • Division of Gastroenterology, Yokohama City University School of Medicine, Japan
    • Yoneda Kyoko
    • Division of Gastroenterology, Yokohama City University School of Medicine, Japan
    • Yoneda Masato
    • Division of Gastroenterology, Yokohama City University School of Medicine, Japan
    • Inamori Masahiko
    • Division of Gastroenterology, Yokohama City University School of Medicine, Japan

Abstract

Although peroxisome proliferator-activated receptor γ (PPARγ) is strongly expressed in the intestinal epithelium, the role of PPARγ in intestinal tumorigenesis has not yet been elucidated. To address this issue, we investigated the effect of PPARγ inhibition and its mechanism on intestinal tumorigenesis using a selective antagonist, T0070907. We treated Apc<sup>Min/+</sup> mice and carcinogen-induced colon cancer model C57BL/6 mice with T0070907 and counted the number of spontaneous polyps and aberrant crypt foci and observed cell proliferation and β-catenin protein in the colon epithelium. To investigate its mechanism, the changes of β-catenin/TCF (T cell factor) transcriptional activity and location of β-catenin induced by T0070907 were investigated in the colon cancer cell lines. T0070907 promoted polyp formation in the small intestine of Apc<sup>Min/+</sup> mice and aberrant crypt foci in the colon of C57BL/6 mice. PPARγ inhibition promoted cell proliferation and increased expressions of the c-myc and cyclin D1 genes and the β-catenin protein in the colon epithelium. In vitro, cell proliferation was promoted, but it was inhibited by the transfection of dominant-negative Tcf4. T0070907 increased β-catenin/TCF transcriptional activity and β-catenin protein in the cytsol and nucleus, but relatively decreased it on the cell membrane. PPARγ antagonist promotes tumorigenesis in the small intestine and colon through stimulation of epithelial cell proliferation. β-Catenin contributes to the promotion of tumorigenesis by PPARγ antagonist due to activation of TCF/LEF (lymphoid enhancer factor) transcriptional factor.<br>

Journal

  • Journal of Pharmacological Sciences

    Journal of Pharmacological Sciences 108(4), 535-544, 2008

    The Japanese Pharmacological Society

Codes

  • NII Article ID (NAID)
    130000075870
  • Text Lang
    ENG
  • ISSN
    1347-8613
  • Data Source
    J-STAGE 
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