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Resistance to Cell Death Induction and its Overcome in Childhood Cancer Cells

Research Project

Project/Area Number 17390301
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionMie University

Principal Investigator

KOMADA Yoshihiro  Mie University, Department of Pediatric and Developmental Science, Professor (80186791)

Co-Investigator(Kenkyū-buntansha) AZUMA Eiichi  Mie University Hospital, Cell Transplantation and Therapy Center, Associate Professor (50211008)
HORI Hiroki  Mie University, Graduate Schoolof Medicine, Department of Pediatric and Developmental Science, Asscoiate Professor (40252366)
Project Period (FY) 2005 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥16,240,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥840,000)
Fiscal Year 2007: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2006: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2005: ¥10,200,000 (Direct Cost: ¥10,200,000)
KeywordsApoptosis / Caspase / Death receptor / Cell cycle / Signal transduction / PI3 Kinase / Akt pathway / MAP Kinase pathway / MAPキナーゼ / サイクリン蛋白 / 抗Fas抗体 / TRAIL
Research Abstract

The activation of caspase-3 and caspase-8 was found to be cell cycle-dependent. Cells expressing active form of caspase-3 were cyclin-A/B1, p27/kip-1 and Ki-67 negative but positive for cyclin E, whereas the expression of active form of caspase-8 was detected in cyclin-A/B1/E and Ki-67 negative cells. In addition, both activation of caspases and Fas-mediated apoptosis were completely abolished when leukemia cells were arrested at early G1 phase of the cell cycle. These results suggested that caspase-3 would be activated in cells entering late G1 or early S phase ; caspase-8 would be activated in middle or late G1 phase.
Phosphoinositide-3-kinase (P13-kinase) /Akt pathway was constitutively active in TRAIL(Tumor necrosis factor-related apoptosis-inducing ligand)-resistant leukemia cells, but not in sensitive cells. Phosphate and tensin homologue deleted on chromosome 10 (PTEN) level was the same in both sensitive and resistant cells, but resistant cells expressed more level of phosphorylated inactive form of PTEN than the sensitive cells. There was induction of apoptosis when resistant cells were treated with a combination of TRAIL and a PI3-kinase inhibitor. These results demonstrated that resistance to TRAIL-induced apoptosis could be induced through phosphorylation of Akt and PTEN.
Mitogen-activated kinase (MAPK) : JNK and p38 were constantly activated in leukemia cells, whereas ERK1/2 phosphorylation was found in 30% of B-lineage or T-lineage leukemia cells. When activation of ERK1/2 were inhibited, significant growth inhibition and cell death were induced. It is assumed that cross-talking among Death receptor-mediated signals, PI3-kinase/Akt pathway and MAPK pathway would be important for decision-making of cellular response to Death receptor stimulation

Report

(4 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • 2005 Annual Research Report

Research Products

(12 results)

All 2007 2006 2005

All Journal Article Presentation

  • [Journal Article] Cell cycle dependency of caspase activation in Fas-induced apoptosis in leukemia cells2007

    • Author(s)
      Yufeng Li, Komada Y, et. al.
    • Journal Title

      Cancer Science 98

      Pages: 1174-1183

    • NAID

      10019539140

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Cell cycle dependency of caspase activation in Fas-induced apoptosis in leukemia cells2007

    • Author(s)
      Li, Y, Dida, F, Iwao, A, Deguchi, T, Azuma, E, Komada, Y
    • Journal Title

      Cancer Science 98(8)

      Pages: 1174-1183

    • NAID

      10019539140

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Cell cycle dependency of caspase activation in Fas-induced apoptosis in leukemia cells2007

    • Author(s)
      Yufeng Li, Komada Y.
    • Journal Title

      Cancer Science 98

      Pages: 1174-1183

    • NAID

      10019539140

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evidence of graft-versus-tumor effect in refractory metastatic neuroblastoma2006

    • Author(s)
      Hirayama M, Komada Y, et. al.
    • Journal Title

      Transplantation 82

      Pages: 142-144

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Evidence of graft-versus-tumor effect in refractory metastatic neuroblastoma2006

    • Author(s)
      Hirayama, M, Azuma, E, Araki, M, Komada, Y, Nakagawa, A
    • Journal Title

      Transplantation 82(1)

      Pages: 142-144

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Acquisition of Fas resistance by Fas receptor mutation in a childhood B-precursor acute lymphoblastic leukemia cell line, MML-12005

    • Author(s)
      Inaba H, Komada Y, et. al.
    • Journal Title

      International Journal of Oncology 27

      Pages: 573-579

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Acquisition of Fas resistance by Fas receptor mutation in a childhood B-precursor acute lymphoblastic leukemia cell line, MML-12005

    • Author(s)
      Inaba, H, Shimada, K, Zhou, YW, Ido, M, Buck, S, Yonehara, S, Kaplan, J, Komada, Y
    • Journal Title

      International Journal of Oncolology 27(2)

      Pages: 573-579

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Cell cycle dependency of caspase activation in Fas-induced apoptosis in leukemia cells2005

    • Author(s)
      李 玉峰, 駒田美弘, 他
    • Journal Title

      日本小児血液学会雑誌 19・5

      Pages: 504-504

    • NAID

      10019539140

    • Related Report
      2005 Annual Research Report
  • [Presentation] Mechanisms of acquired resistance to TRAIL-induced apoptosis in B-lymphocytic leukemia2005

    • Author(s)
      DIDA FRANCIS、駒田美弘
    • Organizer
      第47回日本小児血液学会
    • Place of Presentation
      宇都宮
    • Year and Date
      2005-11-26
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Cell cycle dependent of Fas-mediated cell death in leukaemia cells2005

    • Author(s)
      李 玉峰、駒田美弘
    • Organizer
      第47回日本小児血液学会
    • Place of Presentation
      宇都宮
    • Year and Date
      2005-11-26
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Mechanisms of acquired resistance to TRIAL induced apoptosis in B-lymphocytic leukemia2005

    • Author(s)
      Dida, F, Li, Y, Deguchi, T, Azuma, E, Komada, Y
    • Organizer
      The 47th Annual Meeting of The Japanese Society of Pediatric Hematology
    • Place of Presentation
      Utsunomiya
    • Year and Date
      2005-11-26
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Cell cycle dependent of Fas-mediated cell death in leukaemia cells2005

    • Author(s)
      Li, Y, Dida, F, Deguchi, T, Azuma, E, Komada, Y
    • Organizer
      The 47th Annual Meeting of The Japanese Society of Pediatric Hematology
    • Place of Presentation
      Utsunomiya
    • Year and Date
      2005-11-26
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2005-03-31   Modified: 2016-04-21  

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