PPAR-γ核内受容体分子を標的にした新しい膵癌治療

Material type: 文書・図像類

Author: 太田, 哲生ほか

Publisher: 金沢大学医薬保健研究域医学系

Publication date: 2003-05

Material Format: Digital

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Note (General)：: 転写制御因子であるるperoxisome proliferator activated receptor-γ(PPAR-γ)は、retinoid X receptor(RXR)と二量体を形成し、それぞれのリガンド結合に依存してPPAR応答性部位と呼ばれる特異的なDNA塩基配列に選択的に結合して転写を...

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Material Type: 文書・図像類
Title: PPAR-γ核内受容体分子を標的にした新しい膵癌治療
Author/Editor: 太田, 哲生
Ohta, Tetsuo
Author Heading: 太田, 哲生
Ohta, Tetsuo
Publication, Distribution, etc.: 金沢大学医薬保健研究域医学系
Publication Date: 2003-05
Publication Date (W3CDTF): 2003-05
Alternative Title: A new strategy for the therapy of pancreatic cancer by a specific ligand of peroxisome proliferator-activated receptor-gamma
Periodical title: 平成14(2002)年度科学研究費補助金基盤研究(C) 研究成果報告書 = 2002 Fiscal Year Final Research Report
No. or year of volume/issue: 2000-2002
Volume: 2000-2002
Pages: 5p.-
Text Language Code: jpn
Subject Heading: PPAR-γ核内受容体
thiazolidinedione(TZD)
膵癌
分化誘導療法
G1 growth arrest
p21Waf-1蛋白
E-cadherin蛋白
tumor dormancy therapy
peroxisome proliferator-activated receptor-γ
thiazolidinedione (TZD)
pancreatic cancer
differentiation therapy
p21Waf-1 protein
E-cadherin protein
β-catenin
Target Audience: 一般
Note (General): 転写制御因子であるるperoxisome proliferator activated receptor-γ(PPAR-γ)は、retinoid X receptor(RXR)と二量体を形成し、それぞれのリガンド結合に依存してPPAR応答性部位と呼ばれる特異的なDNA塩基配列に選択的に結合して転写を制御する核内受容体である。我々は、消化器癌のなかでも大腸癌のみならず膵癌にも高率にPPAR-γ蛋白が過剰に発現していることに注目し、PPAR-γ核内受容体分子を標的とした新しい膵癌治療が可能か否かを研究した。[材料]分化度の異なる5種類の膵癌細胞株を使用した。[結果]PPAR-γの特異的リガンドであるthiazolidinedione(TZD)処理により、膵癌細胞の増殖が濃度依存性に抑制(clonogenic assayでのED50値は1-5μM)された。また、cell cycle調節因子であるp21Waf-1蛋白が強く誘導され、cytostatic(flow cytometryでG1 arrestが観察される)に癌細胞の増殖が抑制された。さらに、TZD処理によりE-cadherinの癌細胞膜での発現増強(分化誘導)に伴って、細胞質内のtyrosine phosphorylationを受けたβ-catenin(蛋白量には変化なし)が減少し、β-cateninの局在が細胞質から細胞膜(細胞骨格系蛋白)へとtranslocationした。そして、癌細胞間の接着能亢進により、マトリゲルinvasion assayでも運動・浸潤能は低下した。[まとめ]以上の成績より、PPAR-γ核内受容体を標的にしたTZDによる膵癌治療は、癌細胞の分化誘導を介して膵癌細胞の増殖をcytostaticに抑制し、metastatic phenotypeを減弱させることから、tumor dormancyを誘導する有用な治療法になる可能性が示唆された。
Peroxisome proliferator-activated receptor-γ (PPAR-γ), a transcription factor belonging to the nuclearreceptor superfamily, forms functional heterodimers with the retinoid X receptor. Synthetic PPAR-γ ligands have been shown to inhibit the growth of several human tumor cell lines and to induce growth arrest and differentiation in primary cultures of human liposarcoma, colon cancer, and breast cancer cells in vitro and in vivo. The aim of this study was to examine whether PPAR-γ is expressed at high level in human pancreatic cancer cells, and its ligand can inhibit cellular growth through terminal differentiation of pancreatic cancer cells. In addition, we also examined whether thiazol idinedione (TZD), a potent PPAR-γ ligand. could modulate the E-cadherin/β-catenin system in human pancreatic cancer cells. First, in this study we investigated the expression of PPAR-γ in five pancreatic cancer cell lines: Capan-1(well differentiated adenocarcinema), AsPC-1(moderately differentiated adeno carcinoma), BxPC-3(moderately differentiated adenocarcinoma), Panc-1(poorly differentiated adenocarcinoma), and MIAPaCa-2(undifferentiated carcinoma). All five expressed PPAR-γ mRNA and protein, shown respectively on RT-PCR and Western blotting analisis. Clonogenic assaya showed that TZD completely inhibits colony formation of these cells at a concentration of 10 μ M. Moreover, treatment of these cells with 10 μM TZD resulted in GO/G1 cell cyclearrest. According to Western blotting, TZD markedly increased differentiation markers including E-cadherin and CEA, while β-catenin did not change significantly. In untreated cells, fluorescence immunostaining demonstrated β-catenin predominantly in the cytoplasm and/or nucleus: in TZD-treated cells, β-caten in localization had dramatically shifted to the plasma membrane, in association with increased E-cadherin at this site. Thus, a PPAR-γ ligand appears to participate not only in induction of cell growth and differentiation in pancreatic cancer cells, but also in the regulation of E-cadherin/β-catenin system. Such ligands may prove clinically useful as cytostatic anticancer agents.
研究課題/領域番号:12671213, 研究期間(年度):2000-2002
出典：「PPAR-γ核内受容体分子を標的にした新しい膵癌治療」研究成果報告書　課題番号12671213 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作成
DOI: 10.24517/00050725
Source: https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=44383&item_no=1&attribute_id=26&file_no=1
https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=44383&item_no=1&attribute_id=26&file_no=1
Access Restrictions: 限定公開
Rights (production): CC BY-NC-ND
Related Material: https://kaken.nii.ac.jp/search/?qm=40194170
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671213/
https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-12671213/126712132002kenkyu_seika_hokoku_gaiyo/
Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）
https://irdb.nii.ac.jp
Original Data Provider (Database): 金沢大学 : 金沢大学学術情報リポジトリKURA