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APOPTOSIS BY THE INHIBITION OF TELOMERASE ACTIVITY IN CANCER CELLS

Research Project

Project/Area Number 14570457
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionGifu University

Principal Investigator

UEMATSU Takahiro  GIFU UNIVERSITY, SCHOOL OF MEDICINE, RESEARCH ASSOCIATE, 大学院・医学研究科, 助手 (90334937)

Co-Investigator(Kenkyū-buntansha) MORIWAKI Hisataka  GIFU UNIVERSITY, SCHOOL OF MEDICINE, PROFESSOR, 大学院・医学研究科, 教授 (50174470)
SHIDOJI Yoshihiro  SIEBOLD UNIVERSITY, CELLULAR BIOCHEMISTRY SECTION, PROFESSOR, 看護栄養学部, 教授 (00111518)
SHIRATORI Yoshimune  GIFU UNIVERSITY, SCHOOL OF MEDICINE, ASSOCIATE PROFESSOR, 大学院・医学研究科, 助教授 (20313877)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsRETINOID / HEPATOCELLULAR CARCINOMA / CANCER CHEMOPREVEN / TELOMERASE / APOPTOSIS / CLONAL DELETION / MOLECULAR MARKETTING / NUCLEAR RECEPTOR
Research Abstract

We have conducted investigations of chemoprevention of hepatocellular carcinoma (HCC) by retionoids and confirmed the clinical effects of acyclic retionid on second primary hepatocarcinogenesis. Acyclic retinoid prevents hepatocarcinogenesis by eradicating premalignant and latent malignant clones of transformed cells from the liver. We demonstrate the mechanism of this clonal deletion at the cellular level. Production of albumin was recovered while that of AFP-L3 was reduced after exposure of the cells to acyclic retinoid for 2 days. In parallel, both TERT mRNA expression and telomerase activity were down-regulated. The cells subsequently died due to apoptosis. Serial increases in mitochondrial membrane permeability and caspase-9 and -3 activities induced apoptosis. Acyclic retinoid first induces differentiation and reduces telomerase activity. Subsequent late apoptosis completes the clonal deletion of the cells.
We revealed that acyclic retinoid not only binds to nuclear receptors, but also affects membrane receptors. Acyclic retinoid enhanced anti-tumor effects of not only IFN-β but also IFN-α, however, natural retinoic acid (all-trans and 9-cis retinoic acid) failed to exert such effect. This combination effect was likely due to enhanced apoptosis induction as characterized by DNA fragmentation and chromatin condensation. Pretreatment of the HCC cells with acyclic retinoid followed by IFN-β, but not the converse, induced such cytotoxic effect. Acyclic retinoid increased the expression of type 1 IFN receptor (IFNR) and inclusion with anti-type 1 IFNR antibody abolished the synergistic growth suppression by the combination.
We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (20 results)

All 2004 2002 Other

All Journal Article (13 results) Book (1 results) Publications (6 results)

  • [Journal Article] The ring finger protein, RNF8, interacts with retinoid X receptor ・・ and enhances its transcription-stimulating activity.2004

    • Author(s)
      Takano Y 他
    • Journal Title

      J Biol Chem 279

      Pages: 18926-18934

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Acyclic retinoid, NIK-333, inhibits N-diethylnitrosamine-induced rat hepatocarcinogenesis through suppression of TGF-α expression and cell proliferation.2004

    • Author(s)
      Kagawa M 他
    • Journal Title

      Carcinogenesis 25

      Pages: 979-985

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The ring finger protein, RNF8, interacts with retinoid X receptor α and enhances its transcription-stimulating activity.2004

    • Author(s)
      Takano Y, Adachi S, Okuno M, Muto Y, Yoshioka T, Matsushima-Nishiwaki R, Tsurumi H, Ito K, Friedman SL, Moriwaki H, Kojima S, Okano Y
    • Journal Title

      J Biol Chem 279

      Pages: 18926-18934

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Acyclic retinoid, NIK-333, inhibits N-diethylnitrosamine-induced rat hepatocarcinogenesis through suppression of TGF-α expression and cell proliferation.2004

    • Author(s)
      Kagawa M, Sano T, Ishibashi N, Hashimoto M, Okuno M, Moriwaki H, Suzuki R, Kohno H, Tanaka T
    • Journal Title

      Carcinogenesis 25

      Pages: 979-985

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The ring finger protein, RNF8, interacts with retinoid X receptor α and enhances its transcription-stimulating activity.2004

    • Author(s)
      Takano Y et al.
    • Journal Title

      J Biol Chem 279

      Pages: 18926-18934

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Acyclic retinoid, NIK-333 inhibits N-diethylnitrosamine-induced rat hepatocarcinogenesis through suppression of TGF-α expression and cell proliferation.2004

    • Author(s)
      Kagawa M et al.
    • Journal Title

      Carcinogenesis 25

      Pages: 979-985

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Acyclic retinoid in the chemoprevention of hepatocellular carcinoma2004

    • Author(s)
      Kojima S et al.
    • Journal Title

      Int J Oncol 24

      Pages: 797-805

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Intrahepatic cholangiocarcinoma arising 10 years after the excision of congenital extrahepatic biliary dilation : A case report.2002

    • Author(s)
      Goto N 他
    • Journal Title

      J Gastroenterol 36

      Pages: 856-862

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Acyclic retinoid induces partial differentiation, down-regulates telomerase reverse transcriptase mRNA expression and tolomerase activity, and induces apoptosis in human hepatoma-derived cell lines.2002

    • Author(s)
      Yasuda I 他
    • Journal Title

      J Hepatol 36

      Pages: 660-671

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Synergistic induction of apoptosis by acyclic retinoid and interferon- b in human hepatocellular carcinoma cells.2002

    • Author(s)
      Obora A 他
    • Journal Title

      Hepatology 36

      Pages: 1115-1124

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Intrahepatic cholangiocarcinoma arising 10 years after the excision of congenital extrahepatic biliary dilation : A case report.2002

    • Author(s)
      Goto N, Yasuda I, Uematsu T, Kanemura N, Takai S, Ando K, Kato T, Osada S, Takao H, Saji S, Shimokawa K, Moriwaki H
    • Journal Title

      J Gastroenterol 36

      Pages: 856-862

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Acyclic retinoid induces partial differentiation, down-regulates telomerase reverse transcriptase mRNA expression and telomerase activity, and induces apoptosis in human hepatoma-derived cell lines.2002

    • Author(s)
      Yasuda I, Shiratori Y, Adachi S, Obora A, Takemura M, Okuno M, Shidoji Y, Seishima M, Muto Y, Moriwaki H
    • Journal Title

      J Hepatol 36

      Pages: 660-671

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Synergistic induction of apoptosis by acyclic retinoid and interferon-b in human hepatocellular carcinoma cells.2002

    • Author(s)
      Obora A, Shiratori Y, Okuno M, Adachi S, Takano Y, Matsushima-Nishiwaki R, Yasuda I, Yamada Y, Akita K, Sano T, Shimada J, Kojima S, Okano Y, Friedman SL, Moriwaki H
    • Journal Title

      Hepatology 36

      Pages: 1115-1124

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Chemoprevention of hepatocellular carcinoma with retinoid : Therapy for Viral Hepatitis and Prevention of Hepatocellular Carcinoma.2004

    • Author(s)
      Moriwaki H
    • Total Pages
      8
    • Publisher
      Tokyo, Springer.
    • Related Report
      2004 Annual Research Report
  • [Publications] Toda K.et al.: "Therapeutic effect of intraarterial prednisolone injection in severe intestinal Behcet's disease."J Gastroenterol. 37. 844-848 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Goto N.et al.: "Intrahepatic cholangiocarcinoma arising 10 years after the excision of congenital extrahepatic biliary dilation"J Gastroenterol. 36. 856-862 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] 植松孝広 他: "難治性肝性脳症に対するIVRの長期予後"岐阜県内科医会雑誌. 16. 21-26 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yasuda I: "Acyclic retinoid induces partial differentiation, down-regulates telomerase reverse transcriptase mRNA expression and telomerase activity, and induces apoptosis in human hepatoma-derived cell lines"J Hepatol. 36. 660-671 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Obora A: "Synergistic induction of apoptosis by acyclic retinoid and interferon-β in human hepatocellular carcinoma cells"Hepatology. 36. 1115-1124 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 植松孝広, 森脇久隆: "肝細胞癌「消火器ナビゲーター」滝川 一編"メディカルレビュー社、大阪. 4 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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