Targeting the ERK-MAP kinase pathway in cancer therapy

2009 Fiscal Year Final Research Report

• Project/Area Number: 17016056
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Nagasaki 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
• 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

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.

Research Products

• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
  • Year and Date: 20080000
• [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
  • Year and Date: 20070000
• [Presentation] Targeting the ERK signaling pathway in cancer therapy (2007)
  • 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
  • Year and Date: 20070000
• [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
  • Total Pages: 219-224
  • Publisher: ファルマシア
• [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
  • Total Pages: 107-112
  • Publisher: 南山堂
• [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
  • Total Pages: 13-18
  • Publisher: 南江堂