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2003 Fiscal Year Final Research Report Summary

Aproteasome-p27 system is involved in growth inhibition by PPARγ ligands in GI cancers

Research Project

Project/Area Number 14570438
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionAsahikawa Medical College

Principal Investigator

OKUMURA Toshikatsu  Asahikawa Medical College, Department of General Medicine, Professor, 医学部, 教授 (60281903)

Co-Investigator(Kenkyū-buntansha) TANNO Satoshi  Asahikawa Medical College, Department of General Medicine, Assistant Professor, 医学部, 講師 (30333686)
Project Period (FY) 2002 – 2003
Keywordstroglitazone / cancer / p27Kip1 / proteasome / skp2 / PPARgamma / PPARgamma
Research Abstract

We have demonstrated that peroxisome proliferator activated receptor gamma(PPARr) ligands inhibit cell growth in gastric and pancreatic cancer cells and that p27 accumulation is essential for the growth inhibition by PPAR ligands(Takahashi et al., FEBS Lett 1999,Motomura et al., Cancer Res 2000). In the present study, we tried to clarify the precise mechanisms by which PPAR ligand stimulates the protein expression of p27. Troglitazone, a ligand for PPAR, increased the protein amount of p27 and inhibited cell growth in gastric, pancreatic and hepatic cancer cells. Lactacystin, an proteasome inhibitor, by itself similarly inhibited cell growth and increased p27 protein expression. Troglitazone potently inhibited proteasome activity. These results suggest that PPAR activation by troglitazone inhibits proteasome activity, thereby accumulating p27 protein, which in turn inhibits cell growth. We furthermore demonstrated that troglitazone suppressed skp2, an ubiqutin ligaze, expression. All these results suggest that the growth inhibition by PPAR actibvation was mediated by p27^<Kip1> accumulation which is induced by both inhibition of ubiquitylation of p27^<Kip1> and reduction of degradation activity of p27^<Kip1> by proteasome.

  • Research Products

    (8 results)

All Other

All Publications (8 results)

  • [Publications] Takeuchi S: "Troglitazone induces G1 arrest by p27Kip1 induction that is mediated by inhibition of proteasome in human gastric cancer cells"Jpn J Cancer Res. 93. 774-782 (2002)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nagamine M: "PPARr ligand-induced apoptosis through a p53 dependent mechanism in human gastric cancer cell"Cancer Sci. 94. 338-343 (2003)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Motomura W: "Growth arrest by troglitazone is mediated by p27^<Kip1> accumulation which is resulted from dual inhibition of proteasome activity and Skp2 expression in human hepatocellular carcinoma cells"Int J Cancer. 108. 41-46 (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Motomura W: "Inhibition of cell invasion and morphological change by troglitazone in cultured human pancreatic cancer cells"J Gastroenterol. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeuchi S: "Troglitazone induces G1 arrest by p27Kip1 induction that is mediated by inhibition of proteasome in human gastric cancer cells."Jpn J Cancer Res. 93. 774-782 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagamine M: "PPARr ligand-induced apoptosis through a p53 dependent mechanism in human gastric cancer cell."Cancer Sci. 94. 338-343 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Motomura W: "Growth arrest by troglitazone is mediated by p27^<Kip1> accumulation which is resulted from dual inhibition of proteasome activity and Skp2 expression in human hepatocellular carcinoma cells."Int J Cancer. 108. 41-46 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Motomura W: "Inhibition of cell invasion and morphological change by troglitazone in cultured human pancreatic cancer cells."J Gastroenterol. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2005-04-19  

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