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がん細胞の悪性化を阻害する物質の探索

Research Project

Project/Area Number 12217133
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKeio University

Principal Investigator

井本 正哉  慶應義塾大学, 理工学部, 教授 (60213253)

Co-Investigator(Kenkyū-buntansha) 田代 悦  慶應義塾大学, 理工学部, 助手 (00365446)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥38,000,000 (Direct Cost: ¥38,000,000)
Fiscal Year 2004: ¥7,800,000 (Direct Cost: ¥7,800,000)
Fiscal Year 2003: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 2002: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 2001: ¥8,200,000 (Direct Cost: ¥8,200,000)
Fiscal Year 2000: ¥8,000,000 (Direct Cost: ¥8,000,000)
Keywordsがん細胞 / 異常増殖 / Bcl-2 / アポトーシス / PDGF受容体 / サイクリンD1 / CDC25A / レプトマイシン / 低分子量Gタンパク質 / 浸潤 / ゲラニルゲラニル基合成酵素 / 酵素阻害剤 / 微生物二次代謝産物 / ゲルフェリン / イノシトールリン脂質代謝回転 / イノスタマイシン / ceramide合成 / BH1ドメイン / Bax / ドミナントネガティブ / FGF receptor / プロモーター / E2F-1 / 癌悪性化 / 転移 / 細胞運動 / マイグラスタチン / ムベラスチン / 天然化合物
Research Abstract

がん細胞は、遺伝子変異の蓄積により異常な増殖能、高い浸潤・転移能およびアポトーシス耐性能を獲得することにより悪性化する。そこで、これらを阻害する薬剤の探索と機構解析を行った。
1)Bcl-2機能阻害物質インセドニンの発見
Bcl-2やBcl-xLはアポトーシスを負に制御している蛋白質で、ヒトの半数以上の癌細胞において過剰発現が観察されている。この過剰発現が癌の悪性化に関与しておいることが考えられることからBcl-2の機能阻害物質を微生物の二次代謝産物より探索した。その結果、放線菌1772-21株の培養液に活性を見出した。単離精製および構造解析により新規化合物インセドニンを発見した。Bcl-2を過剰発現させたヒト小細胞肺ガンMs-1細胞はアドリアマイシンやカンプトテシンに対して耐性を示すが、インセドニンの存在下では細胞死が誘導された。
2)新規エキソンを含むPDGF受容体mRNAの発現制御機構と機能解析
サイクリンD1が過剰発現した細胞ではヒト血小板由来増殖因子受容体(PDGF受容体)が転写レベルで上昇していることを見いだした。この機構解析を進めた中から、サイクリンD1/pRB/E2F-1で制御される新規ヒトPDGF受容体mRNAスプライシングバリアントを見いだした。
3)CDC25A阻害物質の探索
CDC25Aは細胞周期を正に制御するタンパク質であることから、CDC25Aの阻害剤は制がん活性が期待できる。合成された数種類のnaphtoquinoneアナログについてCDC25A阻害活性を評価し、いくつかのCDC25Aの阻害活性を有する化合物を見いだした。
4)レプトマイシン感受性タンパク質の同定
HeLa細胞に核外移行阻害剤レプトマイシンBを処理し、核内に蓄積したタンパク質を2次元電気泳動で分離し、MALDI-TOF Massで同定した。およそ80個のタンパク質が同定された。

Report

(5 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (23 results)

All 2005 2004 Other

All Journal Article (2 results) Publications (21 results)

  • [Journal Article] Synthesis of the naphthalene-derived inhibitors against Cdc25A dual-specificity protein phosphatase and their biological activity2005

    • Author(s)
      A.Shinbashi, A.Tsuchiya, M.Imoto, S.Nishiyama
    • Journal Title

      Bioorganic & Medicinal Chemistry Letters 15

      Pages: 61-65

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The synthesis amd Biological activity of pyranonaphthoquione derivative from Streptomyces sp.And their related substances2004

    • Author(s)
      A.Shinbashi, A.Tsuchiya, M.Imoto, S.Nishiyama
    • Journal Title

      Bull.Chem.Soc.Japan 77

      Pages: 1925-1930

    • Related Report
      2004 Annual Research Report
  • [Publications] S.Zenitani et al.: "Gerfelin, a novel inhibitor of geranylgeranyl diphosphate synthase from Beauveria felina QN22047. I. Taxonomy, Fermentation, Isolation, and Biological activities."J.Antibiot.. 56. 617-621 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] S.Zenitani et al.: "Gerfelin, a novel inhibitor of geranylgeranyl diphosphate synthase from Beauveria felina QN22047. II. Structural elucidation."J.Antibiot. 56. 658-660 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] E.Tashiro et al.: "Regulation of FGF receptor-2 expression by transcription factor E2F-1"Oncogene. 22. 5630-5635 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] M.Kawatani et al.: "Deletion of the BH1 Domain of Bcl-2 Accelerates Apoptosis by Acting in a Dominant Negative Fashion"J.Biol.Chem.. 278. 19732-19742 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] M.Kawatani et al.: "Transmembrane domain of Bcl-2 is required for inhibition of ceramide synthesis, but not cytochrome c release in the pathway of inostamycin-induced apoptosis"Exp.Cell Res.. 286. 57-66 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] E, Tashiro et al.: "Overexpression of Cyclin D1 Contributes to Malignancy by Up-Regulation of FGF Receptor 1 via the pRB/E2F Pathway."Cancer Res.. 63. 424-431 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] M.Shintani: "Overexpression of Cyclin D1 Contributes to Malignant Properties of Esophageal Tumor Cells by Increasing VEGF Production and Decreasing Fas Expression"Anticancer Res.. 22. 639-647 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] H.Nakamura: "Absolute Configuration of Migrastatin, a Novel 14-Membered Ring Macrolide"Antibiot.. 55. 442-444 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Y, Yoshimoto: "Induction of EGF-dependent apoptosis by vacuolar-type H^+-ATPase inhibitors in A431 cells overexpressing the EGF receptor"Exp.Cell Res.. 279. 118-127 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Y.Yoshimoto: "Vacuolar-Type H^+-ATPase Inhibitory Activity of Synthetic Analogues of the Concanamycins : Is the Hydrogen Bond Network Involving the Lactone Carbonyl, the Hemiacetal Hydroxy Group, and the C-19 Hydroxy Group Essential for the Biological Activity of the Concanamycins?"Bioorg.Med.Chem.Lett.. 12(24). 3525-3528 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] E.Tashiro: "Overexpression of Cyclin D1 Contributes to Malignancy by Up-Regulation of FGF Receptor 1 via the pRB/E2F Pathway"Cancer Res.. 63(2). 424-431 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] J.Nakazawa: "A novel action of terpendole E on the motor activity of mitotic kinesin Eg5"Chemistry & Biology. 10. 131-137 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] M.Kawatani: "Transmembrane domain of Bcl-2 is required for inhibition of ceramide synthesis, but not cytochrome c release in the pathway of inostamycin-induced apoptosis"Exp.Cell Res.. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] 竹本 靖: "Migrastatin, a novel 14-membered ring macroride, inhibits anchorage-independent growth of human small cell lung carcinoma Ms-1 cells"J.Antibiot.. 54. 1104-1107 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 新谷 雅史: "Overexpression of Cyclin D1 Contributes to Malignant Properties of Esophageal Tumor Cells by Increasing VEGF Production and Decreasing Fas Expression"Anticancer Res. (印刷中).

    • Related Report
      2001 Annual Research Report
  • [Publications] 中栄 功一: "Absolute Configuration of Migrastatin, a Novel 14-Membered Ring Macroiide"J.Antibiot.. (印刷中).

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Nakae: "Migrastatin, a new inhibitor of tumor cell migration from Streptomyces sp.MK929-43F1"J.Antibiot.. 53. 1130-1136 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Nakae: "Migrastatin, a novel 14-membered lactone from Streptomyces sp.MK929-43F1"J.Antibiot.. 53. 1228-1230 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Kawatani: "Involvement of protein kinase C-regulated ceramide generation in inostamycin-induced apoptosis."Exp.Cell Res. 259. 389-397 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.Matsumoto: "Bcl-2-independent induction of apoptosis by neuropeptide receptor antagonist in human small cell lung carcinoma cells"Anticancer Research. 20. 3123-3130 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] N.Endo: "Herbimycin A Induces G1 Arrest through Accumulation of p27 (Kip1) in Cyclin D1-Overexpressing Fibroblasts"Biochem.Biophys.Res.Commun.. 267. 54-58 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2018-03-28  

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