Targeting the ERK-MAP kinase pathway in cancer therapy

2012 Fiscal Year Final Research Report

• Project/Area Number: 22300340
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: Kyoto University (2011-2012); Nagasaki University (2010)
• Principal Investigator: KOHNO Michiaki 京都大学, 薬学研究科, 研究員 (00027335)
• Co-Investigator(Kenkyū-buntansha): OZAKI Kei-ichi 長崎大学, 大学院・医歯薬学総合研究科, 准教授 (50252466) ; TANIMURA Susumu 長崎大学, 大学院・医歯薬学総合研究科, 助教 (90343342)
• Co-Investigator(Renkei-kenkyūsha): UESATO Shin-ichi 関西大学, 工学部, 教授 (50111969)
• Project Period (FY): 2010 – 2012
• 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 / Bcl-2 ファミリー蛋白質

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 and markedly sensitize various humor tumor xenografts to microtubule-destabilizing agent-/HDAC inhibitor-induced cytotoxicity. 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 ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models (2013)
  • Author(s): Sakamoto, T., Ozaki, K., Fujio, K., Kajikawa, S., Uesato, S., Watanabe, K., Tanimura, S., Koji, T. & Kohno, M
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 433 Pages: 456-462
  • Peer Reviewed
• [Journal Article] Central role of the exchange factor GEF-H1 in TNF-α-induced sequential activation of Rac, ADAM17/TACE, and RhoA in tubular epithelial cells. (2013)
  • Author(s): Waheed, F., Dan, Q., Amoozadeh, Y., Zhang, Y., Tanimura, S., Speight, P., Kapus, A. &Szaszi, K.
  • Journal Title: Mol. Biol. Cell Volume: 24 Pages: 1068-1082
  • Peer Reviewed
• [Journal Article] Functional characterization of the novel BRAF complex mutation, BRAF(V600delinsYM), identified in papillary thyroid carcinoma (2013)
  • Author(s): Matsuse, M., Mitsutake, N., Tanimura, S., Ogi, T., Nishihara, E., Hirokawa, M., Fuziwara, C. S., Saenko, V. A., Suzuki, K., Miyauchi, A. & Yamashita, S.
  • Journal Title: Int. J. Cancer Volume: 132 Pages: 738-743
  • Peer Reviewed
• [Journal Article] Inhibition of the p38 MAPK pathway ameliorates renal fibrosis in an NPHP2 mouse model (2012)
  • Author(s): Sugiyama, N., Kohno, M. & Yokoyama, T.
  • Journal Title: Nephrol. Dial. Transplant Volume: 27 Pages: 1351-1358
  • Peer Reviewed
• [Journal Article] Up-regulation of pro-apoptotic protein Bim and down-regulation of anti-apoptotic protein Mcl-1 cooperatively mediate enhanced tumor cell death induced by the combination of ERK kinase (MEK) inhibitor and microtubule inhibitor. (2012)
  • Author(s): Kawabata, T. Tanimura, S., Asai, K., Kawasaki, R., Matsumaru, Y. & Kohno, M.
  • Journal Title: J. Biol. Chem. Volume: 287 Pages: 10289-10300
  • Peer Reviewed
• [Journal Article] Targeting the extracellular signal-regulated kinase pathway in cancer therapy. (2011)
  • Author(s): Kohno, M., Tanimura, S. & Ozaki, K.
  • Journal Title: Biol. Pharm. Bull. Volume: 34 Pages: 1781-1784
  • Peer Reviewed
• [Journal Article] SH3P2 is a negative regulator of cell motility whose function is inhibited by RSK-mediated phosphorylation. (2011)
  • Author(s): Tanimura, S., Hashizume, J., Kurosaki, Y., Sei,K., Gotoh, A., Ohtake, R., Kawano, M., Watanabe, K. & Kohno. M.
  • Journal Title: Genes Cells Volume: 16 Pages: 514-526
  • Peer Reviewed
• [Journal Article] New microtubule polymerization inhibitors comprising a nitrooxymethyl phenyl group. (2011)
  • Author(s): Kawaratani Y., Harada T., Hirata Y., Nagaoka Y., Tanimura S., Shibano M., Taniguchi M., Yasuda M., Baba K. & Uesato S.
  • Journal Title: Bioorg. Med. Chem. Volume: 19 Pages: 3995-4003
  • Peer Reviewed
• [Journal Article] Peumusolide A, 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.
  • Journal Title: Tetrahedron Lett. Volume: 51 Pages: 1678-1681
  • Peer Reviewed
• [Journal Article] Blockade of the extracellularsignal-regulated kinase pathway enhances the therapeutic efficacy of microtubule destabilizing 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 Volume: 16 Pages: 1170-1178
  • Peer Reviewed
• [Presentation] Myosin1E の細胞運動亢進作用はUNC45-Hsp90 複合体による細胞内局在制御によって調節される (2012)
  • Author(s): 谷村 進、 平田弦也、大山 要、中原康子、松丸由美、尾崎惠一、武田弘資、河野通明
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡県
  • Year and Date: 2012-12-15
• [Presentation] UNC45 によるMyosin1E の細胞内局在制御 (2012)
  • Author(s): 平田弦也、 谷村 進、木原康孝、 尾崎惠一、武田弘資、 河野通明
  • Organizer: 第29回日本薬学会九州支部大会
  • Place of Presentation: 熊本県
  • Year and Date: 2012-12-09
• [Presentation] Myosin1E によるカベオラ形成制御と細胞運動 (2012)
  • Author(s): 中原康子、 谷村 進、浜松絢子、尾崎惠一、武田弘資、河野通明
  • Organizer: 第29回日本薬学会九州支部大会
  • Place of Presentation: 熊本県
  • Year and Date: 2012-12-09
• [Presentation] MEK and microtubule inhibitors together kill tumor cells through up-regulation of Bim and down-regulation of Mcl-1 (2012)
  • Author(s): 谷村 進、河野通明
  • Organizer: 第71回日本癌学会学術大会
  • Place of Presentation: 北海道
  • Year and Date: 2012-09-20
• [Presentation] Myosin 1E による細胞運動制御の分子メカニズム (2011)
  • Author(s): 森田和幹、平田弦也、中原康子、 谷村 進、河野通明
  • Organizer: 第28回日本薬学会九州支部大会
  • Place of Presentation: 福岡県
  • Year and Date: 2011-12-10
• [Presentation] Myosin 1E enhances cell motility via the induction of filopodia formation: essential role of phosphorylation on Ser736 (2011)
  • Author(s): 谷村 進、橋詰淳哉、渡邉一石、 河野通明
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知県
  • Year and Date: 2011-10-05
• [Presentation] MEK 阻害剤と微小管重合阻害剤の併用による細胞死誘導増強作用の分子機構 (2010)
  • Author(s): 浅井廣平、川畑拓誠、内山 綾、 谷村 進、河野通明
  • Organizer: 第27回日本薬学会九州支部大会
  • Place of Presentation: 長崎県
  • Year and Date: 2010-12-11
• [Presentation] Myosin 1E による細胞運動制御の分子機構 (2010)
  • Author(s): 大竹里佳、橋詰淳哉、中原康子、 谷村 進、河野通明
  • Organizer: 第27回日本薬学会九州支部大会
  • Place of Presentation: 長崎県
  • Year and Date: 2010-12-11
• [Presentation] 新規細胞運動制御因子 SH3P2 は Myosin 1E と結合する (2010)
  • Author(s): 河野通宏、橋詰淳哉、森田和幹、金丸雄祐、谷村 進、河野通明
  • Organizer: 第27回日本薬学会九州支部大会
  • Place of Presentation: 長崎県
  • Year and Date: 2010-12-11
• [Presentation] 新規タンパク質 SH3P2 による細胞運動制御の分子機構 (2010)
  • Author(s): 谷村 進、大竹里佳、河野通宏、橋詰淳哉、後藤愛依子、黒崎由希子、瀬井香奈子、河野通明
  • Organizer: 第83回日本生化学会大会
  • Place of Presentation: 兵庫県
  • Year and Date: 2010-12-08
• [Presentation] Myosin 1E は invadopodia の形成を介してがん細胞の浸潤を調節する (2010)
  • Author(s): 谷村 進、橋詰淳哉、後藤愛依子、河野通宏、大竹里佳、渡邉一石、河野通明
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪府
  • Year and Date: 2010-09-23
• [Presentation] MEK阻害剤とHDAC阻害剤の併用による抗腫瘍効果増強-Xenograftでの検討- (2010)
  • Author(s): 坂元利彰、藤尾康祐、梶川修平、上里新一、渡邉一石、 谷村 進、 尾崎恵一、河野通明
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪府
  • Year and Date: 2010-09-23
• [Book] 細胞死実験プロトコール (2011)
  • Author(s): 坂元利彰、河野通明
  • Total Pages: 224
  • Publisher: 羊土社