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

Aproteasome-p27 系统参与 PPARγ 配体对胃肠道癌症的生长抑制

• 批准号: 14570438
• 负责人: OKUMURA Toshikatsu
• 金额: $ 2.24万
• 依托单位: Asahikawa Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570438/
• 关键词: troglitazone; cancer; p27Kip1; proteasome; skp2; PPARgamma; PPARgamma; 胃癌; プロテアソーム; 細胞増殖抑制; 分

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.

我们已经证明过氧化物酶体增殖物激活受体γ（PPARr）配体抑制胃癌和胰腺癌细胞中的细胞生长，并且p27积累对于通过PPAR配体的生长抑制是必需的（Takahashi等人，FEBS Lett 1999，Motomura等人，Cancer Res 2000）。在本研究中，我们试图阐明PPAR配体刺激p27蛋白表达的确切机制。在胃癌、胰腺癌和肝癌细胞中，PPAR的配体曲格列酮增加了p27的蛋白量，并抑制了细胞生长。蛋白酶体抑制剂Lactacystin本身同样抑制细胞生长并增加p27蛋白表达。曲格列酮可有效抑制蛋白酶体活性。这些结果表明，通过曲格列酮激活PPAR抑制蛋白酶体活性，从而积累p27蛋白，这反过来又抑制细胞生长。我们进一步证明曲格列酮抑制skp2，一种泛素连接蛋白，表达。这些结果表明，激活PPAR抑制细胞生长是<Kip1>通过抑制p27 α的泛素化<Kip1>和蛋白酶体降低p27 α的降解活性来诱导p27 α<Kip1>的积累而实现的。

项目成果

Takeuchi et al.: "Troglitazone induces G1 arrest by p27Kip1 induction that is mediated by inhibition of proteasome in human gastric cancer cells"Japanese Journal of Cancer Research. 93. 774-782 (2002)

Takeuchi 等人：“曲格列酮通过抑制人胃癌细胞中蛋白酶体介导的 p27Kip1 诱导来诱导 G1 停滞”《日本癌症研究杂志》。

Nagamine M: "PPARr ligand-induced apoptosis through a p53 dependent mechanism in human gastric cancer cell"Cancer Sci. 94. 338-343 (2003)

Nagamine M：“人胃癌细胞中 PPARr 配体通过 p53 依赖性机制诱导细胞凋亡”Cancer Sci。

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)

Motomura W：“曲格列酮的生长停滞是由 p27^<Kip1> 积累介导的，这是人肝细胞癌细胞中蛋白酶体活性和 Skp2 表达的双重抑制造成的”Int J Cancer。

Nagamine et al.: "PPARr ligand-induced apoptosis through a p53 dependent mechanism in human gastric cancer cell"Cancer Sci. (in press). (2003)

Nagamine 等人：“人胃癌细胞中 PPARr 配体通过 p53 依赖性机制诱导细胞凋亡”Cancer Sci。

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)

Takeuchi S：“曲格列酮通过 p27Kip1 诱导来诱导 G1 停滞，p27Kip1 是通过抑制人胃癌细胞中的蛋白酶体介导的”Jpn J Cancer Res。