Study of inhibitors and characterization of naturally occurring spheroids from monolayer culture

2013 Fiscal Year Final Research Report

• Project/Area Number: 23501310
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: Iwate Medical University
• Principal Investigator: UEHARA YOSHIMASA 岩手医科大学, 薬学部, 教授 (50160213)
• Research Collaborator: NISHIYA Naoyuki 岩手医科大学, 薬学部, 講師 (10286867) ; OKU Yusuke 岩手医科大学, 薬学部, 助教 (50626843)
• Project Period (FY): 2011 – 2013
• Keywords: 乳がん幹細胞 / CD133 / ALDH / Her2 / ドキソルビシン / TGF-beta / Wntシグナル / 次世代シーケンサー

Research Abstract

In naturally occurring floating cell mass (spheroids) caused by the high-density culture of a breast cancer cell line, expression of CD133 cancer stem cell marker is increased. Analysis of the gene expression pattern using the next generation sequencers, expression variation of genes involved in the TGF-beta and the Wnt signaling were detected. Increase of aldehyde dehydrogenase activity was also observed. Although, the spheroids are resistant to anti-cancer agents such as doxorubicin, phosphorylation of HER2 is enhanced, and showed a sensitivity of nM order for HER2 inhibitors, such as lapatinib and canertinib.

Research Products

• [Journal Article] Multimodal Effects of Small Molecule ROCK and LIMK Inhibitors on Mitosis, and Their Implication as Anti-Leukemia Agents (2014)
  • Author(s): Oku Y, Tareyanagi C, Takaya S, Osaka S, Ujiie H, Yoshida K, Nishiya N, Uehara Y
  • Journal Title: PLoS One Volume: 9(3) (eCollection 2014) Pages: e92402
  • DOI: 10.1371/journal.pone.0092402
• [Journal Article] Zebrafish Chemical Suppressor Screening Identifies Small Molecule Inhibitors of the Wnt/ β -catenin Pathway (2014)
  • Author(s): Nishiya N, Oku Y, Kumagai Y, Sato Y, Yamaguchi E, Sasaki A, Shoji M, Ohnishi Y, Okamoto H, Uehara Y.
  • Journal Title: Chem. Biol. Volume: 21 [Epub ahead of print] Pages: 530-540
  • DOI: 10.1016/j.chembiol.2014.02.015
• [Journal Article] p38MAPK and Rho-dependent kinase are involved in anoikis induced by anicequol or 25-hydroxycholesterol in DLD-1 colon cancer cells (2013)
  • Author(s): Tanaka AR, Noguchi K, Fukazawa H, Igarashi Y, Arai H, Uehara Y
  • Journal Title: Biochem Biophys Res Commun Volume: 430 (Epub 2012 Dec 22) Pages: 1240-1245
  • DOI: 10.1016/j.bbrc.2012.12.067
• [Journal Article] Identification of LY83583 as a specific inhibitor of Candida albicans MPS1 protein kinase (2011)
  • Author(s): Tsuda K, Nishiya N, Umeyama T and Uehara Y
  • Journal Title: Biochem Biophys Res Commun Volume: 409 (Epub 2011 May 8) Pages: 418-423
  • DOI: 10.1016/j.bbrc.2011.05.010
• [Journal Article] Cytotoxic and EGFR tyrosine kinase inhibitory activities of aglycone derivatives obtained by enzymatic hydrolysis of oleoside-type secoiridoid glucosides, oleuropein and ligustroside (2011)
  • Author(s): Kikuchi M, Mano N, Uehara Y, Machida K, Kikuchi M
  • Journal Title: J Nat Med Volume: 65 (Epub 2010 Nov 2) Pages: 237-240
  • DOI: 10.1007/s11418-010-0476-8
• [Presentation] A phenotype-based screening for chemical suppressors of the Wnt/beta-catenin pathway in zebrafish (2013)
  • Author(s): Nishiya, N., Kawano, T., Uehara, Y.
  • Organizer: The 18th Japanese Foundation for Cancer Research-International Symposium on Cancer Chemotherapy
  • Place of Presentation: Tokyo
  • Year and Date: 2013-12-04
  • Invited
• [Presentation] ゼブラフィッシュ胚を用いたWnt/β-catenin 経路ケミカルサプレッサーの探索 (2013)
  • Author(s): 西谷直之、河野富一、上原至雅
  • Organizer: 日本薬学会生薬天然物部会主催・第5回食品薬学シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2013-11-02
  • Invited
• [Presentation] Geranylgeranyltransferase as a potential molecular target for Wnt/beta-catenin pathway inhibitors (2013)
  • Author(s): Nishiya, N., Oku, Y., Uehara, Y.
  • Organizer: 日本癌学会第72回総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-10-03
• [Presentation] ゲラニルゲラニルトランスフェラーゼ阻害剤によるβ-catenin 核移行の阻害 (2013)
  • Author(s): 西谷直之、奥 裕介、上原至雅
  • Organizer: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2013-06-13
• [Presentation] ROCK-LIMK1はAurora A を活性化し、中心体の恒常性維持に寄与する (2013)
  • Author(s): 奥 裕介、西谷直之、上原至雅
  • Organizer: 第17回日本がん分子標的治療学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2013-06-13
• [Presentation] Geranylgeranyltransferase inhibitors attenuate the Wnt/beta-catenin signaling pathway (2013)
  • Author(s): Nishiya, N., Abe, S., Iwaoka, S., Ohmori, N., Ohnishi, Y., Sasaki, A., Shoji, M., Oku, Y, Uehara, Y.
  • Organizer: FAOBMB mini symposium 2013
  • Place of Presentation: 矢巾
  • Year and Date: 2013-04-06
• [Presentation] ROCK-LIMK1 axis activates Aurora A and participates in centrosome integrity (2013)
  • Author(s): Oku, Y., Tareyanagi, C., Ujiie, H., Takaya, S., Yoshida, K., Nishiya, N., Uehara, Y.
  • Organizer: FAOBMB mini symposium 2013
  • Place of Presentation: 矢巾
  • Year and Date: 2013-04-06
• [Presentation] Wnt/β-catenin 経路阻害活性をもつGGTI-286 の作用機序の解析 (2013)
  • Author(s): 大森紀和、阿部早織、岩岡ささの、大西亨美、佐々木朱里、庄司桃子、奥 裕介、西谷直之、上原至雅
  • Organizer: 第132年会日本薬学会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-28
• [Presentation] Rho-associated coiled coil kinase (ROCK)阻害剤による染色体不安定性の誘導 (2013)
  • Author(s): 垂柳智秋、氏家悠貴、高谷真一、吉田健太郎、奥 裕介、西谷直之、上原至雅
  • Organizer: 第132年会日本薬学会
  • Place of Presentation: 横浜
  • Year and Date: 2013-03-28
• [Presentation] がん細胞と微小環境との相互作用の薬理学的制御 (2013)
  • Author(s): 上原至雅、奥 裕介、西谷直之
  • Organizer: 日本農芸化学会2013年度大会シンポジウム「細胞骨格とシグナル伝達の理解からがんに迫る」
  • Place of Presentation: 仙台
  • Year and Date: 2013-03-27
• [Presentation] IMU14 derivatives as novel Wnt/beta-catenin signaling inhibitors (2012)
  • Author(s): Nishiya, N., Kawano, T., Uehara、Y.
  • Organizer: 日本癌学会 第71回総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-21
• [Presentation] タンパク質脂質修飾による選択的Wnt/β-cateninシグナル制御 (2012)
  • Author(s): 西谷直之, 奥裕介, 上原至雅
  • Organizer: 未来医療開発プロジェクト研究成果発表会
  • Place of Presentation: 岩手医科大学矢巾キャンパス
  • Year and Date: 2012-08-09
• [Presentation] タンパク質の脂質修飾制御による選択的Wnt/β-catenin シグナル阻害 (2012)
  • Author(s): 西谷直之、奥 裕介、上原至雅
  • Organizer: 第16回日本がん分子標的治療学会学術集会
  • Place of Presentation: 北九州
  • Year and Date: 2012-06-29
• [Presentation] 新規Wnt/β-catenin シグナル阻害剤IMU1003 の同定 (2012)
  • Author(s): 小松豊徳、三田地沙織、河野富一、西谷直之、上原至雅
  • Organizer: 第132年会日本薬学会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-29
• [Presentation] カンジダMps1 キナーゼを標的とする新規抗真菌薬の探索 (2012)
  • Author(s): 及川慎吾、加藤大器、今野拓哉、白鳥裕佳、森岡広記、吉池比香里、奥裕介、津田香代子、西谷直之、上原至雅
  • Organizer: 第132年会日本薬学会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-29
• [Presentation] ゼブラフィッシュ胚を用いたWnt/β-catenin 経路阻害剤探索系の構築 (2012)
  • Author(s): 山口英美、熊谷裕介、佐藤佑樹、西谷直之、上原至雅
  • Organizer: 第132年会日本薬学会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-29
• [Presentation] ゼブラフィッシュ胚を用いたWnt/β-catenin シグナル阻害剤の探索 (2011)
  • Author(s): 西谷直之、河野富一、津田香代子、上原至雅
  • Organizer: 日本がん分子標的治療学会第15回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-09-22
• [Patent(Industrial Property Rights)] Wntシグナル阻害剤 (2013)
  • Inventor(s): 西谷直之、上原至雅
  • Industrial Property Rights Holder: 西谷直之、上原至雅
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願2013-141555
  • Filing Date: 2013-07-05
• [Patent(Industrial Property Rights)] 胚の発生および/または分化を制御する方法 (2012)
  • Inventor(s): 西谷直之、河野富一、畠中 稔、上原至雅
  • Industrial Property Rights Holder: 西谷直之、河野富一、畠中 稔、上原至雅
  • Industrial Property Rights Type: PCT
  • Industrial Property Number: JP2012/054585
  • Filing Date: 2012-03-13
  • Overseas