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Analysis of molecular mechanisms of chemoresistance in malignant glioma cells

Research Project

Project/Area Number 14370438
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionKumamoto University

Principal Investigator

SAYA Hideyuki  Kumamoto University, Graduate School of Medical Sciences, Tumor Genetics & Biology, Professor, 大学院・医学薬学研究部, 教授 (80264282)

Co-Investigator(Kenkyū-buntansha) MIMORI Tatsuyuki  Kumamoto University, Graduate School of Medical Sciences, Tumor Genetics & Biology, Associate Professor, 大学院・医学薬学研究部, 助教授 (00117384)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2003: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2002: ¥7,700,000 (Direct Cost: ¥7,700,000)
Keywordsbrain tumor / checkpoint / mitotic catastrophe / chemoresistance / anti-tumor agents / mitosis / DNA damage / cancer / 薬剤抵抗件
Research Abstract

Cell cycle checkpoints prevent transition from one phase of the cell cycle to the next until all processes of the present phase are completed. Defects in the checkpoint functions result in gene mutations and chromosome damages, which contribute to the development and progression of tumors. However, loss of checkpoint function in some cancer cells is considered to be associated with their sensitivity to antineoplastic treatments such as chemotherapy and radiation. Most cancer cells including malignant gliomas are deficient in G_1 checkpoint function and therefore fail to arrest in G_1 phase on exposure to genotoxic agents. Instead, they accumulate temporarily in G_2 phase. However, given that the G_2 checkpoint is also partially impaired in cancer cells, they are unable to maintain G_2 arrest and eventually die as they enter mitosis. This process is known as mitotic catastrophe. The induction of mitotic catastrophe is an important goal of cancer therapies. In the present project, we characterized the dynamics of mitotic catastrophe induced by DNA damage in p53-deficient cancer cells. Most cells entering mitosis with DNA damage arrested at metaphase and subsequently underwent cell death. Furthermore, metaphase arrest prior to the catastrophe was clearly shown to result from activation of the spindle checkpoint, and inhibition of checkpoint function using RNA interference allowed cancer cells to escape mitotic catastrophe. Our findings suggest that the spindle checkpoint function is required for the induction of catastrophe in cancer cells treated with DNA-damaging antineoplastic agents. We speculate that chemoresistance of glioblastomas may be due to the impairment of spindle checkpoint function in those tumors.

Report

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

    (32 results)

All Other

All Publications (32 results)

  • [Publications] Hirota, T, et al.: "Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells."Cell. 114. 585-598 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nitta, et al.: "Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents."Oncogene. (印刷中). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nitta, et al.: "Hyperploidy induced by drugs that inhibit formation of microtubule promotes chromosome instability."Genes Cells. 7. 151-162 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Marumoto, et al.: "Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells"J Biol Chem. 278. 51786-51795 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iida, et al.: "The tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G_1 tetraploidy checkpoint function."Oncogene. (印刷中). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hirota T, Kunitoku N, Sasayama T, Marumoto T, Zhang D, Nitta M, Hatakeyama K, Saya H: "Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells."Cell. 114. 585-598 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nitta M, Kobayashi O, Honda S, Hirota T, Kuninaka S, Marumoto T, Ushio Y, Saya H: "Spindle checkpoint function is required for mitotic catastrophe induced by DNA-damaging agents."Oncogene. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nitta M, Tsuiki H, Arima Y, Harada K, Nishizaki T, Sasaki K, Mimori T, Ushio Y, Saya H: "Hyperploidy induced by drugs that inhibit formation of microtubule promotes chromosome instability."Genes Cells. 7. 151-162 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Marumoto T, Honda S, Hara T, Hirota T, Kohmura B, Saya H: "Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells."J Biol Chem. 278. 51786-51795 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Iida S, Hirota T, Morisaki T, Marumoto T, Hara T, Kuninaka S, Honda S, Kosai K, Kawasuji, Pallas DC, Saya_H: "The tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G_1 tetraploidy checkpoint function."Oncogene. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Honda S, Marumoto T, Hirota T, Nitta M, Arima Y, Ogawa M, Saya H: "Activation of m-calpain is required for chromosome alignment on the metaphase plate during mitosis."J Biol Chem. 279. 10615-10623 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kunitoku N, Sasayama T, Marumoto T, Zhang D, Honda S, Kobayashi O, Hatakeyama K, Ushio Y, Saya H, Hirota T: "Aurora-A-dependent phosphorylation of CENP-A in prophase is essential for concentration of Aurora-B at inner centromeres and for kinetochore function."Dev.Cell. 5. 853-864 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Arima Y, Hirota T, Bronner C, Mousli M, Fujiwara T, Niwa S, Ishikawa H, Saya H: "Downregulation of nuclear protein ICBP90 by p53/p2l^<Cip1/WAF1>-dependent DNA-damage checkpoint signals contributes to cell cycle arrest at G1/S transition"Genes Cells. 9. 131-142 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Murakami D, Okamoto I, Nagano O, Kawano Y, Tomita T, Iwatsubo T, De Strooper B, Yumoto E, Saya H: "Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44."Oncogene. 22. 1511-1516 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sudo T, Nitta M, Saya H, Ueno NT: "Dependence of paclitaxel sensitivity on a functional spindle assembly checkpoint."Cancer Res. 64. 2502-2508 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Fujita N, Watanabe S, Ichimura T, Ohkuma Y, Chiba T, Saya H, Nakao M: "MCAF mediates MBD1-dependent transcriptional repression."Mol Cell Biol. 23. 2834-2843 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yunoue S, Tokuo H, Fukunaga K, Feng L, Ozawa T, Nishi T, Kikuchi A, Hattori S, Kuratsu J, Saya H, Araki N: "Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GAP function toward Ras."J Biol Chem. 278. 26958-26969 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Sugahara KN, Murai T, Nishinakamura H, Kawashima H, Saya H, Miyasaka M: "Hyaluronan oligosaccharides induce CD44 cleavage and promote cell migration in CD44-expressing tumor cells."J Biol Chem. 278. 32259-32265 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yasui Y, Urano T, Kawajiri A, Nagata KI, Tatsuka M, Saya H, Furukawa K, Takahashi T, Izawa I, Inagaki M: "Autophosphorylation of a newly identified site of Aurora-B is indispensable for cytokinesis."J Biol Chem. 279. 12997-13003 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagano O, Murakami D, Hartmann D, De Strooper B, Saftig P, Iwatsubo T, Nakajima M, Shinohara M, Saya H: "Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca^<2+> influx and PKC activation."J Cell Biol. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hirota, T. et al.: "Aurora-A and an interacting activator, the LIM protein Ajuba, are required for mitotic commitment in human cells"Cell. 114. 585-598 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Marumoto, T. et al.: "Aurora-A kinase maintains the fidelity of early and late mitotic events in HeLa cells"J Biol Chem. 278. 51786-51795 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kunitoku, N. et al.: "Aurora-A-dependent phosphorylation of CENP-A in prophase is essential for concentration of Aurora-B at inner centromeres and for kinetochore function"Dev Cell. 5. 853-864 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Murakami, D., et al.: "Presenilin-dependent g-secretase activity mediates the intramembranous cleavage of CD44"Oncogene. 22. 1511-1516 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iida, S., et al.: "The tumor suppressor WARTS ensures genomic integrity by regulating both mitotic progression and G_1 tetraploidy checkpoint function"Oncogene. (印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Honda, S. et al.: "Activation of m-calpain is required for chromosome alignment on the metaphase plate during mitosis"J Biol Chem. (印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nitta, M. et al.: "Hyperploidy induced by drugs that inhibit formation of microtubule promotes chromosome instability"Genes Cells. 7. 151-162 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Morisaki, T. et al.: "WARTS tumor suppressor is phosphorylated by Cdc2/cyclin B at spindle poles during mitosis"FEBS Lett. 529. 319-324 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Okamoto, I., et al.: "Proteolytic Cleavage of CD44 Adhesion Molecule in Multiple Human Tumors"Am J Pathol. 160. 441-447 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Honda, Y., et al.: "Cooperation of HECT-domain ubiquitin ligase hHYD and DNA topoisomerase II-binding protein for DNA damage response"J Biol Chem. 277. 3599-3605 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tojo, M., et al.: "The Aryl hydrocarbon receptor nuclear transporter is modulated by the SUMO-1 conjugating system"J Biol Chem. 277. 46576-46585 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Murakami, D., et al.: "Presenilin-dependent g-secretase activity mediates the intramembranous cleavage of CD44"Oncogene. (印刷中). (2003)

    • Related Report
      2002 Annual Research Report

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

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