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Analysis of activation mechanisms of Rho and RhoGEFs as a new molecular target for lung cancer therapy.

Research Project

Project/Area Number 15590811
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionTottori University

Principal Investigator

CHIKUMI Hiroki  Tottori University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (90283994)

Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2004: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
KeywordsRho / RhoGEF / lung cancer / PDZ-RhoGEF / p115RhoGEF / LARG / RDZ-RhoGEF / Pho
Research Abstract

Rho GTPases play an essential role in the control of various cellular functions. Accumulating evidence suggests that RhoA overexpression contributes to human cancer development. However, the activation states of RhoA are poorly defined in cancer cells. In this study, we examined both the expression levels and the activation states of RhoA and its upstream activator, RhoGEFs, in various lung cancer cells. Additionally, we analyzed the mechanisms of RhoA activation in these cells to search for new molecular targets for lung cancer treatment. We found that RhoA is activated in various lung cancer cells independent of its expression levels. Especially, the activation status of RhoA is higher comparing to its expression levels in small cell lung cancer (SCLC) cells. Next, we measured the expression levels of three RGL-domain containing RhoGEFs: p115RhoGEF, LARG, and PDZ-RhoGEF, as a candidate for direct activator of RhoA in these cancer cells for the first time. We found that LARG is strongly expressed in all types of lung cancer cells, suggesting the importance of LARG in lung cancer pathogenesis. Finally, we dissected the signaling pathway from cell surface receptor to Rho in SCLC cells using broad-spectrum GPCR antagonist and recently reported Gαq-selective inhibitor. We found that the high activation state of RhoA in SCLC cells mainly depends on a neuroendocrine peptide autocrine system which signals through Gα12 coupled GPCR to RhoA. These results suggest that inhibition of this signaling pathway will be the possible new strategies for targeted lung cancer therapy.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (11 results)

All 2005 2004

All Journal Article (11 results)

  • [Journal Article] Suppression of phosphatydylinositol 3-kinase/Akt signaling pathway is a de-terminat of the sensitivity to a novel histone deacylase inhbitor,FK228,in lung adenocarcinima cells2005

    • Author(s)
      Kodani M, Igishi T, Matsumoto S, Chikumi H. et al.
    • Journal Title

      Oncology Reports 13

      Pages: 477-477

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Measurement of Pseudomonas aeruginosa multidrug efflux pumps by quantitative real-time polymerase chain reaction.2005

    • Author(s)
      Yoneda K, Chikumi H. et al.
    • Journal Title

      FEMS Microbiol Lett 243

      Pages: 125-125

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Suppression of phosphatidylinositol 3-kinase/Akt signaling pathway is a determinant of the sensitivity to a novel histone deacetylase inhibitor, FK228, in lung adenocarcinoma cells.2005

    • Author(s)
      Kodani M, Igishi T, Matsumoto S, Chikumi H Shigeoka Y, Nakanishi H, Morita M, Yasuda K Hitsuda Y, Shimizu E.
    • Journal Title

      Oncol Rep. 13(3)

      Pages: 477-477

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Measurement of Pseudomonas aeruginosa multidrug efflux pumps by quantitative real-time polymerase chain reaction.2005

    • Author(s)
      Yoneda K, Chikumi H, Murata T, Gotoh N, Yamamoto H, Fujiwara H, Nishino T, Shimizu E
    • Journal Title

      FEMS Microbiol Lett. 243(1)

      Pages: 125-125

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Down-regulation of inducible nitric oxide synthase by lysophosphatidic acid in human respiratory epithelial cells2004

    • Author(s)
      Kadowaki S, Chikumi H. et al.
    • Journal Title

      Mol Cell Biochem 262

      Pages: 51-51

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cellular immune profile in patients with non-small cell lung cancer after weekly paclitaxel therapy2004

    • Author(s)
      Sako T, Burioka N. et al.
    • Journal Title

      Acta Oncel 43

      Pages: 15-15

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Homo- and hetero-oligomerization of PDZ-RhoGEF,LARG and pll5RhoGEF by their C-terminal region regulates their in vivo Rho GEF activity and transforming potential2004

    • Author(s)
      Chikumi H, Barac A. et al.
    • Journal Title

      Oncogene 23

      Pages: 233-233

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Down-regulation of inducible nitric oxide synthase by lysophosphatidic acid in human respiratory epithelial cells.2004

    • Author(s)
      Kadowaki S, Chikumi H, Yamamoto H, Yoneda K, Yamasaki A, Sato K, Shimizu E.
    • Journal Title

      Mol Cell Biochem. 262(1-2)

      Pages: 51-51

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Cellular immune profile in patients with non-small cell lung cancer after weekly paclitaxel therapy.2004

    • Author(s)
      Sako T, Burioka N, Yasuda K, Tomita K, Miyata M, Kurai J, Chikumi H, Watanabe M, Suyama H, Fukuoka Y, Ueda Y, Shimizu E.
    • Journal Title

      Acta Oncol. 43(1)

      Pages: 15-15

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Homo-and hetero-oligomerization of PDZ-RhoGEF, LARG and p115RhoGEF by their C-terminal region regulates their in vivo Rho GEF activity and transforming potential.2004

    • Author(s)
      Chikumi H, Barac A, Behbahani B, Gao Y, Teramoto H, Zheng Y, Gutkind JS.
    • Journal Title

      Oncogene. 23(1)

      Pages: 233-233

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Suppression of phosphatydylinositol 3-kinase/Akt signaling pathway is a de-terminat of the sensitivity to a novel histone deacylase inhbitor, FK228, in lung adenocarcinima cells2004

    • Author(s)
      Kodani M, Igishi T, Matsumoto S, Chikumi H. et al.
    • Journal Title

      Oncology Reports 13

      Pages: 477-477

    • Related Report
      2004 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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