• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Targeting the ERK-MAP kinase pathway in cancer therapy

Research Project

Project/Area Number 17016056
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionNagasaki University

Principal Investigator

KOHNO Michiaki  Nagasaki University, 大学院・医歯薬学総合研究科, 教授 (00027335)

Co-Investigator(Kenkyū-buntansha) OZAKI Kei-ichi  長崎大学, 大学院・医歯薬学研究科, 准教授 (50252466)
TANIMURA Susumu  長崎大学, 大学院・医歯薬学研究科, 助教 (90343342)
Project Period (FY) 2005 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥45,000,000 (Direct Cost: ¥45,000,000)
Fiscal Year 2009: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2008: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2007: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2006: ¥9,000,000 (Direct Cost: ¥9,000,000)
Fiscal Year 2005: ¥9,000,000 (Direct Cost: ¥9,000,000)
Keywords細胞がん化 / がん化学療法 / ERK-MAPキナーゼ経路 / MEK阻害剤 / 微小管重合阻害剤 / HDAC 阻害剤 / 併用療法 / HDAC阻害剤 / 動物個体系 / ERK-MAPキナーゼ路 / 活性酸素種 / ERK-MAPキナーゼ系 / PI3キナーゼ / Akt系 / チューブリン重合阻害剤 / Xenograft
Research Abstract

Specific blockade of the ERK pathway by MEK inhibitors alone induces mostly cytostatic rather than pro-apoptotic effects, resulting in a limited therapeutic efficacy of MEK inhibitors. However, MEK inhibitors specifically enhance the induction of apoptosis by microtubule-destabilizing agents and HDAC inhibitors in various tumor cells with aberrant activation of the ERK pathway. Our results clearly indicate that administration of both a MEK inhibitor and a microtubule-destabilizing agent/HDAC inhibitor represents a promising chemotherapeutic strategy with improved safety for cancer patients.

Report

(6 results)
  • 2009 Annual Research Report   Final Research Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • 2005 Annual Research Report
  • Research Products

    (51 results)

All 2010 2009 2008 2007 2006 2005

All Journal Article (38 results) (of which Peer Reviewed: 12 results) Presentation (8 results) Book (5 results)

  • [Journal Article] Blockade of the extracellular signal-regulated kinase pathway enhances the therapeutic efficacy of microtubuledestabilizing agents in human tumor xenograft models.2010

    • Author(s)
      Watanabe, K., Tanimura, S., Uchiyama, A., Sakamoto, T., Kawabata, T., Ozaki, K., Kohno, M.
    • Journal Title

      Clin. Cancer Res. 16

      Pages: 1170-1178

    • Related Report
      2009 Final Research Report
  • [Journal Article] Blockade of the ERK or PI3K-Akt signaling pathway enhances the cytotoxicity of histone deacetylase inhibitors in tumor cells resistant to gefitinib or imatinib.2010

    • Author(s)
      Ozaki, K., Kosugi, M., Baba, N., Fujio, K., Sakamoto, T., Kimura, S., Tanimura, S., Kohno, M.
    • Journal Title

      Biochem. Biophys. Res. Commun. 391

      Pages: 1610-1615

    • NAID

      120006983583

    • Related Report
      2009 Final Research Report
  • [Journal Article] unprecedented NES non-antagonistic inhibitor for nuclear export of MEK.2010

    • Author(s)
      Tamura, S., Hattori, Y., Kaneko, M., Shimizu, N., Tanimura, S., Kohno, M., Murakami, N. Peumusolide A
    • Journal Title

      Tetrahedron Lett. 51

      Pages: 1678-1681

    • Related Report
      2009 Final Research Report
  • [Journal Article] Blockade of the ERK or PI3K-Akt signaling pathway enhances the cytotoxicity of histone deacetylase inhibitors in tumor cells resistant to gefitinib or imatinib.2010

    • Author(s)
      Ozaki, K.
    • Journal Title

      Biochem.Biophys.Res.Commun. 391

      Pages: 1610-1615

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blockade of the extracellular signal-regulated kinase pathway enhances the therapeutic efficacy of microtubule-destabilizing agents in human tumor xenograft models.2010

    • Author(s)
      Watanabe, K.
    • Journal Title

      Clin.Cancer Res. 16

      Pages: 1170-1178

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Peumusolide A, unprecedented NES non-antagonistic inhibitor for nuclear export of MEK.2010

    • Author(s)
      Tamura, S.
    • Journal Title

      Tetrahedron Lett. 51

      Pages: 1678-1681

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GEF-H1 mediates tumor necrosis factor-α-induced Rho activation and myosin phosphorylation: Role in the regulation of tubular paracellular permeability.2009

    • Author(s)
      Kakiashvili, E., Speight, P., Waheed, F., Seth, R., Lodyga, M., Tanimura, S., Kohno, M., Rotstein, O.D., Kapus, A., Szaszi, K.
    • Journal Title

      J. Biol. Chem. 284

      Pages: 11454-11466

    • Related Report
      2009 Final Research Report
  • [Journal Article] Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells.2009

    • Author(s)
      Tanimura, S., Uchiyama, A., Watanabe, K., Yasunaga, M., Inada, Y., Kawabata, T., Iwashita, K., Noda, S., Ozaki, K., Kohno, M.
    • Journal Title

      Biochem. Biophys. Res. Commun. 378

      Pages: 650-655

    • NAID

      120006983970

    • Related Report
      2009 Final Research Report
  • [Journal Article] GEF-H1 mediates tumor necrosis factor-α-induced Rho activation and myosin phosphorylation : Role in the regulation of tubular paracellular permeability.2009

    • Author(s)
      Kakiashvili, E.
    • Journal Title

      J.Biol.Chem. 284

      Pages: 11454-11466

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blockade of constitutively activated ERK signaling enhances cytotoxicity of microtubule-destabilizing agents in tumor cells2009

    • Author(s)
      Tanimura, S.
    • Journal Title

      Biochem. Biophys. Res. Commun 378巻

      Pages: 650-655

    • NAID

      120006983970

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] GEF-H1 mediates tumor necrosis factor-α-induced Rho activation and myosin phosphorylation : Role in the regulation of tubular paracellular permeability2009

    • Author(s)
      Kakiashvili, E.
    • Journal Title

      J. Biol. Chem 284巻(印刷中)(掲載確定)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide exchange activity toward RhoA.2008

    • Author(s)
      Fujishiro, S., Tanimura, S., Mure, S., Kashimoto, Y., Watanabe, K, Kohno, M.
    • Journal Title

      Biochem. Biophys. Res. Commun. 368

      Pages: 162-167

    • Related Report
      2009 Final Research Report
  • [Journal Article] Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging drugs.2008

    • Author(s)
      Ozaki, K., Kishikawa, F., Tanaka, M., Sakamoto, T., Tanimura, S, Kohno, M.
    • Journal Title

      Cancer Sci. 99

      Pages: 376-384

    • NAID

      10024002722

    • Related Report
      2009 Final Research Report
  • [Journal Article] Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging drugs2008

    • Author(s)
      Ozaki, K.
    • Journal Title

      Cancer Sci 99巻

      Pages: 376-384

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ERK1/2 phosphorylate GEF-H1 to enhance its guanine nucleotide exchange activity toward RhoA2008

    • Author(s)
      Fujishiro, S.
    • Journal Title

      Biochem. Biophys. Res. Commun 368巻

      Pages: 162-167

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging drugs.2008

    • Author(s)
      Ozaki, K.
    • Journal Title

      Cancer Sci. 99

      Pages: 376-384

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anticancer drugs up-regulate HspBP1 and thereby antagonize the prosurvival function of Hsp70 in tumor cells.2007

    • Author(s)
      Tanimura, S., Hirano, A., Hashizume, J., Yasunaga, M., Kawabata, T., Ozaki, K, Kohno, M.
    • Journal Title

      J. Biol. Chem. 282

      Pages: 35430-35439

    • Related Report
      2009 Final Research Report
  • [Journal Article] Blockade of the phosphatidylinositol 3-kinase-Akt signaling pathway enhances induction of apoptosis by microtubuledestabilizing agents in tumor cells in which the pathway is constitutively activated.2007

    • Author(s)
      Fujiwara, Y., Hosokawa, Y., Watanabe, K., Tanimura, S., Ozaki, K, Kohno, M.
    • Journal Title

      Mol. Cancer Ther. 6

      Pages: 1133-1142

    • Related Report
      2009 Final Research Report
  • [Journal Article] Enantioselective total synthesis of (+)- Ottelione A, (-)-Ottelione B, (+)-3-epi- Otterlione A and preliminary evaluation of antitumor activity.2007

    • Author(s)
      Araki, H., Inoue, M., Suzuki, T., Yamori, T., Kohno, M., Watanabe, K., Abe, H., Katoh, T.
    • Journal Title

      Chem. Eur. J. 13

      Pages: 9866-9881

    • Related Report
      2009 Final Research Report
  • [Journal Article] Requirement of ERK MAP kinase in mouse preimplantation development.2007

    • Author(s)
      Maekawa, M., Yamamoto, T., Kohno, M., Takeichi, M., Nishida, E.
    • Journal Title

      Development 134

      Pages: 2751-2759

    • Related Report
      2009 Final Research Report
  • [Journal Article] Requirement of ERK MAP kinase in mouse preimplantation development.2007

    • Author(s)
      Maekawa, M.
    • Journal Title

      Development 134

      Pages: 2751-2759

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enantioselective total synthesis of (+)-Ottelione A, (-)-Ottelione B, (+)-3-epi-Otterlione A and preliminary evaluation of antitumor activity.2007

    • Author(s)
      Araki, H.
    • Journal Title

      Chem. Eur. J. 13

      Pages: 9866-9881

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anticancer drugs up-regulate HspBP1 and thereby antagonize the prosurvival function of Hsp70 in tumor cells.2007

    • Author(s)
      Tanimura, S.
    • Journal Title

      J. Biol. Chem. 282

      Pages: 35430-35439

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Blockade of the phosphatidylinositol 3-kinase-Akt signaling pathway enhances induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the pathway is constitutively activated.2007

    • Author(s)
      Fujiwara, Y.
    • Journal Title

      Mol. Cancer Ther. 6巻(印刷中)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Targeting the ERK signaling pathway in Cancer Therapy. Ann.2006

    • Author(s)
      Kohno, M., Pouyssegur, J.
    • Journal Title

      Medicine 38

      Pages: 200-211

    • Related Report
      2009 Final Research Report
  • [Journal Article] Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death.2006

    • Author(s)
      Ozaki, K., Minoda, A., Kishikawa, F, Kohno, M.
    • Journal Title

      Biochem. Biophys. Res. Commun. 339

      Pages: 1171-1177

    • Related Report
      2009 Final Research Report
  • [Journal Article] Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death.2006

    • Author(s)
      Ozaki, K.
    • Journal Title

      Biochem. Biophys. Res. Commun. 339巻

      Pages: 1171-1177

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Inhibition of the PI3 kinase/Akt pathway enhances doxorubicin-induced apoptotic cell death in tumor cells in a p53-dependent manner.2006

    • Author(s)
      Fujiwara, Y.
    • Journal Title

      Biochem. Biophys. Res. Commun. 340巻

      Pages: 560-566

    • Related Report
      2006 Annual Research Report
  • [Journal Article] ERK inhibition slows disease progression in mice with polycystic kidney disease.2006

    • Author(s)
      Omori, S.
    • Journal Title

      J. Am. Soc. Nephrol. 17巻

      Pages: 1604-1614

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Targeting the ERK signaling pathway in Cancer Therapy2006

    • Author(s)
      Kohno, M.
    • Journal Title

      Ann. Medicine 38巻

      Pages: 200-211

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death.2006

    • Author(s)
      Ozaki, K.
    • Journal Title

      Biochem.Biophys.Res.Commun. 339巻

      Pages: 1171-1177

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Inhibition of the PI3 kinase/Akt pathway enhances doxorubicin-induced apoptotic cell death in tumor cells in a p53-dependent manner.2006

    • Author(s)
      Fujiwara, Y.
    • Journal Title

      Biochem.Biophys.Res.Commun. 340巻

      Pages: 560-566

    • Related Report
      2005 Annual Research Report
  • [Journal Article] ERK inhibition slows disease progression in mice with polycystic kidney disease.2006

    • Author(s)
      Omori, S.
    • Journal Title

      J.Am.Soc.Nephrol. 17巻(印刷中)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Suppression of tumor cell invasiveness by hydrolysable tannins (plant polyphenols) via the inhibition of matrix metalloproteinase-2/ -9 activity.2005

    • Author(s)
      Tanimura, S., Kadomoto, R., Tanaka, T., Zhang, Y., Kouno, I, Kohno, M.
    • Journal Title

      Biochem. Biophys. Res. Commun. 330

      Pages: 1306-1313

    • Related Report
      2009 Final Research Report
  • [Journal Article] Efficient Suppression of Fibroblast Growth Factor-2-induced ERK Activation by the Cooperative Interaction among Mammalian Sprouty Isoforms.2005

    • Author(s)
      Ozaki, K., Miyazaki, S., Tanimura, S, Kohno, M.
    • Journal Title

      J. Cell Sci. 118

      Pages: 5861-5871

    • Related Report
      2009 Final Research Report
  • [Journal Article] Suppression of tumor cell invasiveness by hydrolysable tannins (plant polyphenols) via the inhibition of matrix metalloproteinase-2/-9 activity.2005

    • Author(s)
      Tanimura, S.
    • Journal Title

      Biochem.Biophys.Res.Commun. 330巻

      Pages: 1306-1313

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Constitutive activation of the 41- and 43-kDa mitogen-activated protein (MAP) kinases in the progression of prostate cancer to an androgen-independent state.2005

    • Author(s)
      Oka, H.
    • Journal Title

      Int.J.Urol. 12巻

      Pages: 899-905

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Efficient suppression of Fibroblast Growth Factor-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms.2005

    • Author(s)
      Ozaki, K.
    • Journal Title

      J.Cell Sci. 118巻

      Pages: 5861-5871

    • Related Report
      2005 Annual Research Report
  • [Presentation] SH3P2はMyosin 1Eの機能制御を介して細胞運動を阻害する2009

    • Author(s)
      谷村進
    • Organizer
      第68回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2009-10-03
    • Related Report
      2009 Annual Research Report
  • [Presentation] PI3キナーゼ/Akt経路遮断はセラミド蓄積を増大させることでドキソルビシンの細胞障害作用を増強する2009

    • Author(s)
      尾崎恵一
    • Organizer
      第68回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2009-10-01
    • Related Report
      2009 Annual Research Report
  • [Presentation] ERK-MAPキナーゼ経路の遮断はがん細胞のスピンドルチェックポイントの感受性を増大させる2008

    • Author(s)
      内山綾
    • Organizer
      第67回日本癌学会学術総会
    • Place of Presentation
      名古屋
    • Year and Date
      2008-10-29
    • Related Report
      2008 Annual Research Report
  • [Presentation] 低酸素環境下における癌細胞の抗癌剤耐性獲得の分子機構2008

    • Author(s)
      尾崎恵一
    • Organizer
      第67回日本癌学会学術総会
    • Place of Presentation
      名古屋
    • Year and Date
      2008-10-29
    • Related Report
      2008 Annual Research Report
  • [Presentation] Blockade of the ERK pathway enhances the antitumor activity of microtubule-destabilizing agents in vitro and in vivo.2008

    • Author(s)
      Watanabe, K., Tanimura, S., Yasunaga, M. Uchiyama, A, Kohno, M.
    • Organizer
      AACR Annual Meeting 2008
    • Place of Presentation
      San Diego
    • Related Report
      2009 Final Research Report
  • [Presentation] ERK-MAPキナーゼ経路の選択的遮断を基盤としたがん化学療法の開発2007

    • Author(s)
      河野通明
    • Organizer
      第66回日本がん学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-04
    • Related Report
      2007 Annual Research Report
  • [Presentation] Blockade of the PI3-kinase-Akt signaling pathway enhances induction of apoptosis by microtubule- destabilizing agents in tumor cells in which the pathway is constitutively activated.2007

    • Author(s)
      Watanabe, K., Fujiwara, Y., Tanimura, S., Ozaki, K, Kohno, M.
    • Organizer
      AACR Annual Meeting 2007
    • Place of Presentation
      Los Angeles
    • Related Report
      2009 Final Research Report
  • [Presentation] Targeting the ERK signaling pathway in cancer therapy2007

    • Author(s)
      河野通明、谷村進、尾崎惠一、渡邊一石
    • Organizer
      第65回日本癌学会総会
    • Place of Presentation
      横浜
    • Related Report
      2009 Final Research Report
  • [Book] 細胞内シグナル伝達経路の選択的遮断を基盤としたがん治療戦略2008

    • Author(s)
      尾崎恵一、谷村進、河野通明
    • Publisher
      ファルマシア
    • Related Report
      2009 Final Research Report
  • [Book] シグナル伝達- 1. MAPキナーゼ経路, がんの分子標的治療(鶴雄隆編)2008

    • Author(s)
      河野通明
    • Publisher
      南山堂
    • Related Report
      2009 Final Research Report
  • [Book] がんの分子標的治療(鶴尾隆編集)2008

    • Author(s)
      河野通明(分担執筆)
    • Publisher
      南山堂
    • Related Report
      2008 Annual Research Report
  • [Book] シグナル伝達系, 新臨床腫瘍学(日本臨床腫瘍学会編)2006

    • Author(s)
      河野通明
    • Publisher
      南江堂
    • Related Report
      2009 Final Research Report
  • [Book] 新臨床腫瘍学-がん薬物療法専門医のために-(分担執筆)2006

    • Author(s)
      日本臨床腫瘍学会(編集)
    • Total Pages
      809
    • Publisher
      南江堂
    • Related Report
      2006 Annual Research Report

URL: 

Published: 2005-04-01   Modified: 2018-03-28  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi