A systematic approach to achieve glioblastoma cure via targeting glioma stem cells

• Project/Area Number: 24390338
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• 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): SATO ATSUSHI 山形大学, 医学部, 助教 (30455901)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2014: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2013: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2012: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: glioma-initiating cell / 神経膠芽腫 / グリオーマ / 腫瘍形成能 / 分化誘導 / 薬剤

Outline of Final Research Achievements

In this project, we searched for drugs that are capable of differentiating glioblastoma stem cells into non-stem glioblastoma cells. Here we discovered that an anti-diabetic drug metformin induces the differentiation of glioblastoma stem cells into non-stem glioblastoma cells through the activation of FoxO3a. Furthermore, we discovered that JNK, a serine/threonine kinase implicated in cellular signaling, plays an essential role in the maintenance of glioblastoma stem cells and also demonstrated that a JNK inhibitor has a differentiation-inducing activity against glioblastoma stem cells.

Research Products

• [Journal Article] GSKJ4, a selective Jumonji H3K27 demethylase inhibitor, effectively targets ovarian cancer stem cells (2015)
  • Author(s): Sakaki et al.
  • Journal Title: Anticancer Research Volume: 35 Pages: 6607-6614
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Differential contribution of ROS to resveratrol-induced cell death and loss of self-renewal capacity of ovarian cancer stem cells. (2015)
  • Author(s): Seino M, et al.
  • Journal Title: Anticancer Research Volume: 35 Pages: 85-96
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Targeting the facilitative glucose transporter GLUT1 inhibits the self-renewal and tumor-initiating capacity of cancer stem cells. (2015)
  • Author(s): Shibuya K, et al.
  • Journal Title: Oncotarget Volume: 6 Pages: 651-661
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] JNK suppression of chemotherapeutic agents-induced ROS confers chemoresistance on pancreatic cancer stem cells. (2015)
  • Author(s): Suzuki S, et al.
  • Journal Title: Oncotarget Volume: 6 Pages: 458-470
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Targeting the K-Ras - JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation. (2014)
  • Author(s): Okada M, et al.
  • Journal Title: Oncotarget Volume: 5 Pages: 5100-5112
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Requirement of JNK signaling for self-renewal and tumor-initiating capacity of ovarian cancer stem cells. (2014)
  • Author(s): Seino M, et al.
  • Journal Title: Anticancer Research Volume: 34 Pages: 4723-4731
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells (2013)
  • Author(s): Okada et al.
  • Journal Title: Oncol Rep Volume: 30 Pages: 1957-1964
  • Peer Reviewed
• [Journal Article] JNK signaling in the control of the tumor-initiating capacity associated with cancer stem cells (2013)
  • Author(s): Kitanaka et al.
  • Journal Title: Genes Cancer Volume: 4 Pages: 388-396
  • Peer Reviewed
• [Journal Article] JNK signaling in the control of the tumor-initiating capacity associated with cancer atem cells (2013)
  • Author(s): Kitanaka C
  • Journal Title: Genes & Cancer
  • Peer Reviewed
• [Journal Article] Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. (2012)
  • Author(s): Sato A et al. (第三著者)
  • Journal Title: Stem Cells Transl Med. Volume: 1 Issue: 11 Pages: 811-24
  • DOI: 10.5966/sctm.2012-0058
  • Peer Reviewed
• [Journal Article] Targeting JNK for therapeutic depletion of stem-like glioblastoma cells (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 Issue: 1 Pages: 516-516
  • DOI: 10.1038/srep00516
  • Peer Reviewed
• [Presentation] グリオーマ、固形がん幹細胞を標的とする治療法開発を目指したがん幹細胞研究 (2015)
  • Author(s): 北中 千史
  • Organizer: 第７４回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] 臨床応用を目指したがん幹細胞研究 (2014)
  • Author(s): 北中 千史
  • Organizer: 第15回日本分子脳神経外科学会
  • Place of Presentation: 山形（大手門パルズ）
  • Year and Date: 2014-09-25
  • Invited
• [Presentation] グリオーマ幹細胞 (2014)
  • Author(s): 北中 千史
  • Organizer: 第32回日本脳腫瘍病理学会
  • Place of Presentation: 徳島（徳島県郷土文化会館）
  • Year and Date: 2014-05-24
  • Invited
• [Presentation] グリオーマ幹細胞 (2014)
  • Author(s): 北中 千史
  • Organizer: 第34回日本脳神経外科コングレス総会
  • Place of Presentation: 大阪（大阪国際会議場）
  • Year and Date: 2014-05-17
  • Invited
• [Presentation] A549非小細胞肺癌細胞の腫瘍形成能維持におけるJNKの特異的な役割 (2013)
  • Author(s): 岡田雅司他
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] メトホルミンによるAMPK-FOXO3経路を介したグリオーマ幹細胞の制御 (2013)
  • Author(s): 佐藤篤他
  • Organizer: 日本脳神経外科学会第72回学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
• [Presentation] 脳腫瘍のcell biology ～グリオーマ幹細胞～ (2012)
  • Author(s): 北中 千史
  • Organizer: 日本脳腫瘍病理学会
  • Place of Presentation: 名古屋国際会議場(名古屋)
  • Year and Date: 2012-05-25