Overcoming therapy resistance of glioma via elucidation of the mechanisms underlying glioma stem cell maintenance

• Project/Area Number: 21390402
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Yamagata University
• Principal Investigator: KITANAKA Chifumi 山形大学, 医学部, 教授 (70260320)
• Co-Investigator(Kenkyū-buntansha): NEMOTO Kenji 山形大学, 医学部, 教授 (10208291)
• Co-Investigator(Renkei-kenkyūsha): SUNAYAMA Jun 山形大学, 医学部, 助教 (80466606) ; TOMIYAMA Arata 山形大学, 医学部, 助教 (40385810) ; TACHIBANA Ken 山形大学, 医学部, 助教 (10400540)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2011: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2010: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2009: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
• Keywords: 脳腫瘍学 / グリオーマ / 幹細胞 / 治療耐性 / 悪性脳腫瘍 / 造腫瘍能 / PI3K / mTOR

Research Abstract

In this study, we searched for intracellular signals as well as signaling molecules involvedin the maintenance of glioblastoma stem cells and demonstrated critical roles for PI3K/mTOR and MAPK in glioblastoma stem cell maintenance. Significantly, PI3K/mTORand MAPK acted on a common molecule, i.e., the FOXO3 transcription factor, whoseactivity was restrained through phosphorylation by these kinases in glioblastoma stemcells. Our results suggest that FOXO3 as well as these kinases could be rational moleculartargets for stem cell-targeted glioblastoma therapies.

Research Products

• [Journal Article] Targeting JNK for therapeutic depletion of stem-like glioblastomacells (2012)
  • Author(s): Matsuda K, Sato A, Okada M, Shibuya K, Seino S, Suzuki K, Watanabe E, Narita Y, Shibui S, Kayama T, Kitanaka C
  • Journal Title: Sci Rep Volume: 2 Pages: 516-516
  • Peer Reviewed
• [Journal Article] Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK (2012)
  • Author(s): Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K, Suzuki K, Narita Y, Shibui S, Kayama T, Kitanaka C
  • Journal Title: Stem Cells Transl Med Volume: 1 Pages: 811-824
  • Peer Reviewed
• [Journal Article] MEK-ERK signaling dictates DNA-repair gene MGMT expression and temozolomide resistance of stem-like glioblastoma cells via the MDM2-p53 axis (2011)
  • Author(s): Sato A, Sunayama J, Matsuda K, Seino S, Suzuki K, Watanabe E, Tachibana K, Tomiyama A, Kayama T, Kitanaka C
  • Journal Title: StemCells Volume: 29 Pages: 1942-1951
  • Peer Reviewed
• [Journal Article] FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity (2011)
  • Author(s): Sunayama J, Sato A, Matsuda KI, Tachibana K, Watanabe E, Seino S, Suzuki K, Narita Y, Shibui S, Sakurada K, Kayama T, Tomiyama A, Kitanaka C
  • Journal Title: Stem Cells Volume: 29 Pages: 1327-1337
  • Peer Reviewed
• [Journal Article] Establishment of a novel monoclonal antibody SMab-1 specific for IDH1 R132S mutation (2011)
  • Author(s): Kaneko MK, Tian W, Takano S, Suzuki H, Sawa Y, Hozumi Y, Goto K, Yamazaki K, Kitanaka C, Kato Y
  • Journal Title: Biochem Biophys Res Commun Volume: 406 Pages: 608-613
  • Peer Reviewed
• [Journal Article] MEK-ERK signaling dictates DNA-repair gene MGMT expression and temozolomide resistance of stem-like glioblastoma cells via the MDM2-p53 axis (2011)
  • Author(s): Sato A
  • Journal Title: Stem Cells Volume: 29 Issue: 12 Pages: 1942-1951
  • DOI: 10.1002/stem.753
  • Peer Reviewed
• [Journal Article] Crosstalk between the PI3K/mTOR and MEK/ERK pathways involved in the maintenance of self-renewal and tumorigenicity of glioblastoma stem-like cells (2010)
  • Author(s): Sunayama J, Matsuda KI, Sato A, Tachibana K, Suzuki K, Narita Y, Shibui S, Sakurada K, Kayama T, Tomiyama A, Kitanaka C
  • Journal Title: StemCells Volume: 28 Pages: 1930-1939
  • Peer Reviewed
• [Journal Article] Dual blocking of mTor and PI3K elicits a pro-differentiation effect on glioblastoma stem like-cells (2010)
  • Author(s): Sunayama J, Sato A, Matsuda KI, Tachibana K, Suzuki K, Narita Y, Shibui S, Sakurada K, Kayama T, Tomiyama A, Kitanaka C
  • Journal Title: Neuro-Oncol Volume: 12 Pages: 1205-1219
  • Peer Reviewed
• [Journal Article] MEK-ERK-dependent multiple caspase activation via mitochondrial proapoptotic Bcl-2 family proteins is essential for heavy ion irradiation-induced glioma celldeath (2010)
  • Author(s): Tomiyama A, Tachibana K, Suzuki K, Seino S, Sunayama J, Matsuda KI, Sato A, Matsumoto Y, Nomiya T, Nemoto K, Yamashita H, Kayama T, Ando K, Kitanaka C
  • Journal Title: Cell Death Dis Volume: 1
  • Peer Reviewed
• [Journal Article] Association of stem cell marker CD133 expression with dissemination of glioblastomas (2010)
  • Author(s): Sato A, Sakurada K, Kumabe T, Sasajima T, Beppu T, Asano K, Ohkuma H, Ogawa A, Mizoi K, Tominaga T, Kitanaka C, Kayama T
  • Journal Title: Neurosurg Rev Volume: 33 Pages: 175-184
  • Peer Reviewed
• [Journal Article] Regulation of neural stem/progenitor cell maintenance by PI3K and mTOR (2010)
  • Author(s): Sato A, Sunayama J, Matsuda KI, Tachibana K, Sakurada K, Tomiyama A, Kayama T, Kitanaka C
  • Journal Title: Neurosci Lett Volume: 410 Pages: 115-120
  • Peer Reviewed
• [Journal Article] Regulation of neural stem/progenitor cell maintenance by PI3K and mTOR (2010)
  • Author(s): Sato A, et al
  • Journal Title: Neurosci Lett Volume: 470 Pages: 115-120
  • Peer Reviewed
• [Journal Article] Association of stem cell marker CD133 expression with dissemination of glioblastomas (2010)
  • Author(s): Sato A, et al
  • Journal Title: Neurosurg Rev Volume: 33 Pages: 175-183
  • Peer Reviewed
• [Presentation] グリオーマ幹細胞に着目した脳腫瘍研究-治療への応用を目指して- (2012)
  • Author(s): 北中千史
  • Organizer: 第1回Neuro-OncologyWest研究会
  • Place of Presentation: 大阪(ヒルトン大阪)
  • Year and Date: 2012-12-08
• [Presentation] グリオーマ幹細胞 (2012)
  • Author(s): 北中千史
  • Organizer: 第7回鹿児島脳腫瘍セミナー特別講演
  • Place of Presentation: 鹿児島(城山観光ホテル)
  • Year and Date: 2012-11-16
• [Presentation] グリオーマ幹細胞 (2012)
  • Author(s): 北中千史
  • Organizer: 第5回玄海脳腫瘍セミナー特別講演
  • Place of Presentation: 福岡(ソラリア西鉄ホテル)
  • Year and Date: 2012-07-06
• [Presentation] グリオーマ幹細胞の維持に関わる分子機構 (2012)
  • Author(s): 北中千史
  • Organizer: 第3回東京前立腺会議招待講演
  • Place of Presentation: 東京(帝国ホテル)
  • Year and Date: 2012-07-05
• [Presentation] 脳腫瘍のcell biology-グリオーマ幹細胞- (2012)
  • Author(s): 北中千史
  • Organizer: 第30回日本脳腫瘍病理学会生涯教育セミナー
  • Place of Presentation: 名古屋(名古屋国際会議場)
  • Year and Date: 2012-05-25
• [Presentation] グリオーマ幹細胞-診断/治療への応用を目指して- (2012)
  • Author(s): 北中千史
  • Organizer: 第45回東北脳腫瘍研究会研究会特別講演
  • Place of Presentation: 仙台(江陽グランドホテル)
  • Year and Date: 2012-04-07
• [Presentation] グリオーマ幹細胞に着目した脳腫瘍研究-診断治療への応用を目指して- (2012)
  • Author(s): 北中千史
  • Organizer: 第66回山形脳神経外科懇話会特別講演
  • Place of Presentation: 山形(パレスグランデール)
  • Year and Date: 2012-01-28
• [Presentation] グリオーマ幹細胞における FoxO3aを介した分化と造腫瘍能の制御 (2011)
  • Author(s): 佐藤篤,砂山潤,松田憲一朗,立花研,渡部江梨子,清野静香,鈴木香,成田善孝,渋井壮一郎,富山新太,北中千史,嘉山孝正
  • Organizer: 第29回日本脳腫瘍学会学術総会
  • Place of Presentation: 下呂(水明館)
  • Year and Date: 2011-11-27
• [Presentation] Glioma stem cell-Dissecting the molecular mechanism involved in the maintenance of stem-like glioblastoma cells for future application to glioblastoma treatment- (2011)
  • Author(s): Kitanaka C
  • Organizer: The 24^<th> International Symposium on Cancer Research
  • Place of Presentation: Tokyo (National Cancer Center)
  • Year and Date: 2011-11-23
• [Presentation] グリオブラストーマ克服を夢見て脳神経外科専門医が迷い込んだ道-グリオーマ幹細胞研究を中心に- (2011)
  • Author(s): 北中千史
  • Organizer: 第3回山梨脳腫瘍研究会
  • Place of Presentation: 甲府(富士屋ホテル)
  • Year and Date: 2011-10-21
• [Presentation] グリオーマ幹細胞におけるMGMT発現制御の分子機構に関する検討 (2011)
  • Author(s): 佐藤篤,松田憲一朗,砂山潤,清野静香,鈴木香,渡部江梨子,立花研,富山新太,北中千史,嘉山孝正
  • Organizer: 第12回日本分子脳神経外科学会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2011-10-15
• [Presentation] 腫瘍幹細胞仮説はグリオブラストーマに根治をもたらすか? (2011)
  • Author(s): 北中千史
  • Organizer: 第70回日本脳神経外科学会総会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2011-10-13
• [Presentation] MEK経路阻害によるMGMT発現およびテモゾロミド感受性に関する検討 (2011)
  • Author(s): 佐藤篤,松田憲一朗,砂山潤,清野静香,鈴木香,櫻田香,立花研,富山新太,北中千史,嘉山孝正
  • Organizer: 第70回日本脳神経外科学会総会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2011-10-12
• [Presentation] Molecular pathways 野宮琢磨(NOMIYA TAKUMA)involved in the maintenance and 山形大学・医学部・助教differentiation of stem-like研究者番号: 60436201glioblastoma cells (2011)
  • Author(s): Kitanaka C
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋(名古屋国際会議場)
  • Year and Date: 2011-10-03
• [Presentation] MEK inhibition enhances temozolomide sensitivity of glioma stem-like cells via MGMTdown-regulation (2011)
  • Author(s): Sato A, Matsuda KI, Sunayama J, Sakurada K, Tachibana K, Tomiyama A, Kitanaka C, Kayama T
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋(名古屋国際会議場)
  • Year and Date: 2011-10-03
• [Presentation] Glioma stem cell – Dissecting the molecular mechanism involved in the maintenance of stem-like glioblastoma cells for future application to glioblastoma treatment - (2011)
  • Author(s): Kitanaka C
  • Organizer: The 24th International Symposium on Cancer Research
  • Place of Presentation: National Cancer Center (Tokyo)
  • Invited
• [Presentation] Molecular pathways involved in the maintenance and differentiation of stem-like glioblastoma cells (2011)
  • Author(s): Kitanaka C
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Invited
• [Presentation] 腫瘍幹細胞仮説はグリオブラストーマに根治をもたらすか？ (2011)
  • Author(s): 北中千史
  • Organizer: 第70回日本脳神経外科学会総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Invited
• [Presentation] 脳外科専門医が基礎医学研究者になってしまった理由（わけ） (2011)
  • Author(s): 北中千史
  • Organizer: 筑波大学大学院人間総合科学研究科医学セミナー
  • Place of Presentation: 筑波大学（筑波）
  • Invited
• [Presentation] グリオブラストーマ克服を夢見て脳神経外科専門医が迷い込んだ道 ～グリオーマ幹細胞研究を中心に～ (2011)
  • Author(s): 北中千史
  • Organizer: 第3回山梨脳腫瘍研究会
  • Place of Presentation: 甲府富士屋ホテル（甲府）
  • Invited
• [Presentation] グリオーマ幹細胞における MGMT発現とテモゾロミド感受性に関する検討 (2010)
  • Author(s): 佐藤篤 ,松田憲一朗 ,砂山潤 ,清野静香 ,鈴木香 ,櫻田香 ,立花研 ,富山新太 ,北中千史 ,嘉山孝正
  • Organizer: 第28回日本脳腫瘍学会
  • Place of Presentation: 軽井沢(軽井沢プリンスホテル)
  • Year and Date: 2010-11-28
• [Presentation] Regulation of neural stem/progenitor cell maintenance by PI3K and mTOR (2010)
  • Author(s): Sato A, Sunayama J, Matsuda KI, Tachibana K, Sakurada K, Tomiyama A, Kayama T, Kitanaka C
  • Organizer: The 18^<th> International Conference on Brain Tumor Research and Therapy
  • Place of Presentation: Travemuende (Gran Spa Resort Arosa Travemuende)
  • Year and Date: 2010-03-18
• [Presentation] フリーラジカル産生を超えた、ミトコンドリアと腫瘍の新たな関係 (2010)
  • Author(s): 北中千史
  • Organizer: 日本分子脳腫瘍学会
  • Place of Presentation: 仙台(艮陵会館記念ホール)(招待講演)
• [Presentation] フリーラジカル産生を超えた、ミトコンドリアと腫瘍の新たな関係 (2010)
  • Author(s): 北中千史
  • Organizer: 日本分子脳神経外科学会
  • Place of Presentation: 仙台