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Analysis of mechanisms for resistance against TRAIL induced apoptosis in gastrointestinal cancer and development of new strategy for cancer therapy using TRAIL

Research Project

Project/Area Number 14570486
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionSapporo Medical University

Principal Investigator

TAKIMOTO Rishu  Sapporo Medical University, Instructor, 医学部, 助手 (10336399)

Co-Investigator(Kenkyū-buntansha) KATO Junji  Sapporo Medical University, Associate Professor, 医学部, 助教授 (20244345)
NIITSU Yoshiro  Sapporo Medical University, Professor, 医学部, 教授 (10045502)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥3,300,000 (Direct Cost: ¥3,300,000)
KeywordsTRAIL / cFLIP / DR5
Research Abstract

AIM : TRAIL is a new member of death ligand which induces apoptosis in a number of cancers including gastrointestinal cancers. However, some cancers are refractory to TRAIL-induced apoptosis, and it is important to clarify the mechanisms of resistance against TRAIL. In this study, we used retrovirus library to examine the molecular mechanisms of TRAIL-induced apoptosis. METHODS and RESULTS ; We examined the sensitivity to TRAIL using a set of cancer cell lines. Two out of four showed sensitivity to TRAIL at low concentration, but others are resistant to TRAIL. We transduced retrovirus library into the sensitive cell line, SW480, and screened the clone to identify the molecule which inhibits TRAIL-mediated apoptosis. Two sets of screening revealed that cELIP is one of the molecules which can block TRAIL signaling. We found two other molecules can be the candidate, but still under examination. In order to augment the sensitivity to TRAIL, we knocked down cFLIP in SKOV3 cells using siRNA and succeeded to sensitize the cells to TRAIL. We then co-treated the cells with p53 modifying drug, CP31398, which induces DR5 expression, and found augmentation of TRAIL sensitivity. CONCLUSION : Down regulation of cFLIP by siRNA or up-regulation of DR5 will overcome the resistance against TRAIL and is expected to apply for clinical study.

Report

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

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Terui T, Murakami K, Takimoto R, et al.: "Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors."Cancer Res.. 63. 8948-8954 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Wang W, Takimoto R, Rastinejad F, El-Deiry WS.: "Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding."Mol Cell Biol.. 23. 2171-2181 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takimoto R, Wang W, Dicker DT, et al.: "The mutant p53-conformation modifying drug, CP-31398,can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein."Cancer Biol Ther.. 1. 47-55 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kuroda H, Matsunaga T, Takimoto R, et al.: "Decrease of Smad4 gene expression in patients with essential thrombocythaemia may cause an escape from suppression of megakarypoiesis by transforming growth factor-beta1."Br J Haematol.. 124. 211-220 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kato J, Sato Y, Takimoto R, et al.: "Ethanol induces transforming growth factor-alpha expression in hepatocytes, leading to stimulation of collagen synthesis by hepatic stellate cells."Alcohol Clin Exp Res.. 58S-63S (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsunaga T, Takemoto N, Takimoto R, et al.: "Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia."Nat Med.. 9. 1158-1165 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Terui T, Murakami K, Takimoto R, et al.: "Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors."Cancer Res.. 63. 9848-9854 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Wang W, Takimoto R, Rastinejad F, El-Deiry WS.: "Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 2Oor MDM2 binding."Mol Cell Biol.. 23. 2171-2181 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takimoto R, Wang W, Dicker DT, et al.: "The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein."Cancer Biol Ther.. 1. 47-55 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kuroda H, Matsunaga T, Takimoto R, et al.: "Decrease of Smad4 gene expression in patients with essential thrombocythaemia may cause an escape from suppression of megakaryopoiesis by transforming growth factor-betal."Br J Haematol.. 124. 211-220 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kato J, Sato Y, Takimoto R, et al.: "Ethanol induces transforming growth factor-alpha expression in hepatocytes, leading to stimulation of collagen synthesis by hepatic stellate cells."Alcohol Clin Exp Res.. 58S-63S (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Matsunaga T, Takemoto N, Takimoto R, et al.: "Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia."Nat Med.. 9. 1158-1165 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Terui T, Murakami K, Takimoto R, et al.: "Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors"Cancer Res.. 63. 8948-8954 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kuroda H, Matsunaga T, Takimoto R, et al.: "Decrease of Smad4 gene expression in patients with essential thrombocy thaemia may cause an escape from suppression of megakaryopoiesis by transforming growth factor-beta1"Br J Haematol.. 124. 211-220 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hisai H, Kato J, Takimoto, R, et al.: "Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity"Clin Cancer Res.. 9. 4852-4859 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kato J, Sato Y, Takimoto R, et al.: "Ethanol induces transforming growth factor-alpha expression in hepatocytes, leading to stimulation of collagen synthesis by hepatic stellate cells"Alcohol Clin Exp Res.. 58S-63S (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kobune M, Kawano Y, Takimoto R, et al.: "Telomerized human multipotent mesenchymal cells can differentiate into hematopietic and cobblestone area-supporting cells"Exp Hematol.. 31. 715-722 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsunaga T, Takemoto N, Takimoto R, et al.: "Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive actor for minimal residual disease of acute myelogenous leukemia"Nat Med.. 9. 1158-1165 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] MacLachlan, T.K., Takimoto, R., et al.: "BRCA1 directs a selective p53-dependent transcriptional response towards growth arrest and DNA repair targets"Mol Cell Biol. 22. 4280-4292 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takimoto, R., MacLachlan, T.K., et al.: "BRCA1 Transcriptionally Regulates Damaged DNA Binding Protein (DDB2) in the DNA Repair Response Following UV-irradiation"Cancer Biol Ther. 1. 177-186 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kato, J., Takimoto, R., et al.: "Ratio of Transferrin (Tf) to Tf-receptor complex in circulation differs depending on Tf Iron saturation"Clin Chem 2002,48 : 181-183.. 48. 181-186 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Wang, W., Takimoto, R., et al.: "CP-31398 Stabilizes Wild-type p53 Protein by Inhibiting its Ubiquitination without Inducing Serine 20 Phosphorylation or Reduced Interaction with MDM2"Mol. Cell. Biol.. (In press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sasaki, H., Takimoto, R., et al.: "Induction of Heat Shock Protein 47 Synthesis by TGF-beta and IL-1beta Via Enhancement of the Heat Shock Element Binding Activity of Heat Shock Transcription Factor 1"J Immunol. 168. 5178-5183 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takimoto, R., Wang, W., et al.: "The Mutant p53-Conformation Modifying Drug, CP-31398, Can Induce Apoptosis of Human Cancer Cells and Can Stabilize Wild-Type p53 Protein"Cancer Biol Ther. 1. 47-55 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takimoto, R., El-Deiry, W.S.: "Role of p53 in regulation of death receptors. Death Receptors in Human Cancer"The Humana Press Inc., New Jersey(in press). (2003)

    • Related Report
      2002 Annual Research Report

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

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