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The mechanism of apoptosis induction by TGF-β stimuli and its clinical application

Research Project

Project/Area Number 13670157
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionAichi Cancer Center

Principal Investigator

OSADA Hirotaka  Aichi Cancer Center Research Institute, Division of Molecular Oncology, Section Head, 分子腫瘍学部, 室長 (30204176)

Co-Investigator(Kenkyū-buntansha) TAKAHASHI Takashi  Aichi Cancer Center Research Institute, Division of Molecular Oncology, Chief, 分子腫瘍学部, 部長 (50231395)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2001: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordshepatoma / TGF-β / Apoptosis / 肝癌
Research Abstract

We studied the mechanism of apoptosis induction by TGF-β stimuli for the purpose of applying in the cancer therapy. We established several apoptosis-inducible and -uninducible subclones derived from the single hepatoma cell line, which were partially sensitive to TGF-β stimuli. Our preliminary study using apoptosis-specific cDNA arrays showed that the expression of TNF family members were induced by TGF-β stimuli in the apoptosis-inducible subclones. We studied further the signaling pathways from TGF-β stimuli to apoptosis. After TGF-β stimuli, DNA contents, expression of TNF family, and activation of caspase family were sequentially studied. At first, the G1/G2 arrest was transiently observed, and then the induction of TNF family expression, caspase-8 activation, and apoptosis induction occurred sequentially. We studied the effects of neutralizing antibodies against TNF family members and caspase-8 inhibitor, Z-IETD-FMK against the apoptosis induction, and obtained about 50% inhibition of apoptosis. The NF- κB reporter analysis also showed the activation of NF-κB pathway by TGF-β stimuli. Our studies demonstrated the signaling pathway from TGF-β to apoptosis through TNF family induction and caspase-8 activation. Furhter studies using high-density cDNA array may be required to reveal the whole pathways of apoptosis induction. The activation of NF-κB might be associated with the TGF-β -resistance, but it remains to be determined.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] Osada H, Tatematsu Y, et al.: "Frequent and histological type-specific inactivation of 14-3-3s in human lung cancers"Oncogene. 21. 2418-2424 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Osada H, Takahashi T: "Genetic alterations of multiple tumor suppressors an oncogenes in the carcinogenesis and progression of lung cancer"Oncogene. 21. 7421-7434 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yatabe Y, Osada H, et al.: "Decreased expression of 14-3-3sigma in neuroendocrine tumors is independent of origin and malignant potential"Oncogene. 21. 8310-8319 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Konishi, H., et al.: "Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at distal 17p13.3 in human lung cancer"Oncogene. 22. 1892-1905 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mizuno K, Osada H, et al.: "Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers"Oncogene. 21. 2328-2333 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koshikawa K, Osada H, et al.: "Significant up-regulation of a novel gene, CLCP1, in a highly metastatic lung cancer subline as well as lung cancers in vivo"Oncogene. 21. 2822-2828 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Konishi H. et al.: "Identification of frequent G2 checkpoint inpairment and a homozygous deletion of 14-3-3e at 17p13.3 in small cell lung cancers"Cancer Research. 62. 271-276 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Osada H, Tatematsu Y, et al.: "Heterogeneous transforming growth factor (TGF)-b unresponsiveness and loss of TGF-b receptor type II expression caused by histone deacetylation in lung cancer cell lines"Cancer Research. 61. 8331-8339 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masuda A, Osada H, et al.: "Protective function of p27(KIP1) against-apoptosis in small cell lung cancer cells in unfavorable microenvironments"American Journal of Pathology. 158. 87-96 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Haruki N, et al.: "Persistent Increase in Chromosome Instability in Lung Cancer : Possible Indirect Involvement of p53 Inactivation"American Journal of Pathology. 159. 1345-1352 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kozaki K, et al.: "Multi-faceted analyses of a highly metastatic human lung cancer cell line NCI-H460-LNM35 suggest mimicry of inflammatory cells in metastasis"Oncogene. 20. 4228-4234 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Haruki N, et al.: "Molecular Analysis of the Mitotic Checkpoint Genes BUB1, BUR1 and BUB3 in Human Lung Cancers"Cancer Letters. 162. 201-205 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Osada H, Tatematsu Y, Yatabe Y, Nakagawa T, Konishi H, Harano T, Tezel E, Takada M, and Takahashi T: "Frequent and histological type-specific inactivation of 14-3-3ο in human lung cancers"Oncogene. 21. 2418-2424 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Osada H and Takahashi T: "Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer"Oncogene. 21. 7421-7434 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yatabe Y, Osada H. Tatematsu Y, Mitsudomi T, and Takahashi T: "Decreased expression of 14-3-3ο in neuroendocrine tumors is independent of origin and malignant potential"Oncogene. 21. 8310-8319 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Konishi, H., Sugiyama, M., Mizuno, K., Saito, H., Yatabe, Y., Takahashi, T., Osada. H., and Takahashi T: "Detailed characterization of a homozygously deleted region corresponding to a candidate tumor suppressor locus at distal 17p13.3 in human lung cancer"Oncogene. 22. 1892-1905 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mizuno K, Osada H, Konishi H, Tatematsu Y, Yatabe Y, Mitsudomi T, Fujii Y, and Takahashi T: "Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers"Oncogene. 21. 2328-2333 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Koshikawa K, Osada H. Kozaki K, Konishi H, Masuda A, Tatematsu Y, Mitsudomi T, Nakao A, Takahashi T: "Significant up-regulation of a novel gene, CLCP1, in a highly metastatic lung cancer subline as well as lung cancers in vivo"Oncogene. 21. 2822-2828 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Konishi H, Nakagawa T, Harano T, Mizuno K, Saito H, Masuda A, Matsuda H, Osada H, and Takahashi T: "Identification of frequent G_2 checkpoint impairment and a homozygous deletion of 14-3-3 ε at 17p13.3 in small cell lung cancers"Cancer Res.. 62. 271-276 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Osada H, Tatematsu Y, Masuda A, Saito T, Sugiyama M, Yanagisawa K,and Takahashi T: "Heterogeneous transforming growth factor (TGF)-β unresponsiveness and loss of TGF-β receptor type II expression caused by histone deacetylation in lung cancer cell lines"Cancer Res.. 61. 8331-8339 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masuda A, Osada H, Yatabe Y, Kozaki K, Tatematsu Y, Takahashi T, Hida T, Takahashi T, and Takahasi T: "Protective function of p27(KIP1) against apoptosis in small cell lung cancer cells in unfavorable microenvironments"Am. J Pathol.. 158. 87-96 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Haruki N, Harano T, Masuda A, Kiyono T, Takahashi T, Tatematsu Y, Shimizu S, Mitsudomi T, Konishi H, Osada H, Fujii Y, and Takahashi T: "Persistent Increase in Chromosome Instability in Lung Cancer : Possible Indirect Involvement of p53 Inactivation"Am. J Pathol.. 159. 1345-1352 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kozaki K, Koshikawa K, Tatematsu Y, Miyaishi O, Saito H, Hida T, Osada H, and Takahashi T: "Multi-faceted analyses of a highly metastatic human lung cancer cell line NCI-H460-LNM35 suggest mimicry of inflammatory cells in metastasis"Oncogene.. 20. 4228-4234 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Haruki N, Saito H, Harano T, Nomoto S, Takahashi T, Osada H, Fujii Y, and Takahashi T.: "Molecular Analysis of the Mitotic Checkpoint Genes BUB1, BUBR1 and BUB3 in Human Lung Cancers"Cancer Letters. 162. 201-205 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Osada H, et al.: "Frequent and histological type-specific inactivation of 14-3-3sigma in human lung cancers"Oncogene. 21・15. 2418-2424 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Osada H, Takahashi T.: "Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and procession of lung cancer"Oncogene. 21・48. 7421-7434 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yatabe Y, Osada H, et al.: "Decreased expression of 14-3-3sigma in neuroendocrine tumors is independent of origin and malignant potential"Oncogene. 21・54. 8310-8319 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Koshikawa K, Osada H, et al.: "Significant up-regulation of a novel gene, CLCP1, in a highly metastatic lung cancer subline as well as in lung cancers in vivo"Oncogene. 21・18. 2822-2828 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Mizuno K, Osada H, et al.: "Aberrant hypermethylation of the CHFR prophase checkpoint gene in human lung cancers"Oncogene. 21・15. 2328-2333 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Konishi H, et al.: "Identification of frequent G(2) checkpoint impairment and a homozygous deletion of 14-3-3epsilon at 17p13.3 in small cell lung cancers"Cancer Res.. 62・1. 271-276 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Osada H, et al.: "Frequent and histological Type-specific inactivation of 14-3-3σ in human lung cancers"Oncogene. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Konishi H, Osada H, et al.: "Identification of frequent G(2) checkpoint impairment and a homozygous deletion of 14-3-3ε At 17p13.3 in small cell lung cancers"Cancer Research. 62. 271-276 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Osada H, et al.: "Heterogeneous transforming growth factor (TGF)-β unresponsiveness and loss of TGF-β receptor type II expression caused by histone deacetylation in lung cancer cell lines"Cancer Research. 61. 8331-8339 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Haruki N, Osada H, et al.: "Persistent increase in chromosome instability in lung cancer : possible indirect involvement of p53 inactivation"American Journal of Pathology. 159. 1345-1352 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kozaki K, Osada H, et al.: "Multi-faceted analyses of a highly metastatic human lung cancer cell line NCI-H460-LNM35 suggest mimicry of inflammatory cells in metastasis"Oncogene. 20. 4228-4234 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Masuda A, Osada H, et al.: "Protective function of p27(KIP1) against apoptosis in small cell lung cancer cells in unfavorable microenvironments"American Journal of Pathology. 158. 87-96 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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