microRNA regulates mTORC2 activity in glioma cells

• Project/Area Number: 24791501
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cerebral neurosurgery
• Research Institution: Kobe University
• Principal Investigator: TANAKA Kazuhiro 神戸大学, 医学(系)研究科(研究院), 助教 (70467661)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: グリオーマ / mTORC2 / microRNA / がん代謝 / グルタミン / mTOR / miRNA / グルタミン代謝

Research Abstract

mTOR signaling is frequently deregulated in cancer including malignant gliomas. We analyzed if a specific microRNA(miR) controls the expression of Rictor, a main component of mTOR Complex 2. Unfortunately, over-expression of miR-137 or 218 mimic in U87 and U251 glioma cells didn't affect the level of Rictor.
Although the PI3K/mTOR pathway is a master regulator of aerobic glycolysis and cellular biosynthesis, the effect of modulating mTOR activity on other metabolic processes, such as glutamine metabolism is not well understood. Metabolic profiling using gas chromatography and mass spectroscopy (GC/MS) and gene expression analysis of key enzymes for glycolysis and glutaminolysis using RT-PCR methods demonstrated the mTOR-targeted treatments (rapamycin or PP242) regulated glycolysis and stimulated glutamine utilization to elicit a switch in the pathways used to deliver glutamine carbon to the tricarboxylic acid (TCA) cycle.

Research Products

• [Journal Article] mTOR Complex 2 Controls Glycolytic Metabolism in Glioblastoma through FoxO Acetylation and Upregulation of c-Myc. (2013)
  • Author(s): Masui K, Tanaka K, Akhavan D, Babic I, Gini B, Matsutani T, Iwanami A, Liu F, Villa GR, Gu Y, Campos C, Zhu S, Yang H, Yong WH, Cloughesy TF, Mellinghoff IK, Cavenee WK, Shaw RJ, Mischel PS.
  • Journal Title: Cell Metab. Volume: 18(5) Issue: 5 Pages: 726-39
  • DOI: 10.1016/j.cmet.2013.09.013
  • Peer Reviewed
• [Journal Article] EGFR Mutation-Induced Alternative Splicing of Max Contributes to Growth of Glycolytic Tumors in Brain Cancer. (2013)
  • Author(s): Babic I, Anderson ES, Tanaka K, Guo D, Masui K, Li B, Zhu S, Gu Y, Villa GR, Akhavan D, Nathanson D, Gini B, Mareninov S, Li R, Camacho CE, Kurdistani SK, Eskin A, Nelson SF, Yong WH, Cavenee WK, Cloughesy TF, Christofk HR, Black DL, Mischel PS.
  • Journal Title: Cell Metab. Volume: 17(6) Issue: 6 Pages: 1000-8
  • DOI: 10.1016/j.cmet.2013.04.013
  • Peer Reviewed
• [Journal Article] (2013)
  • Author(s): Nakamizo S, Sasayama T, Shinohara M, Irino Y, Nishiumi S, Nishihara M, Tanaka H, Tanaka K, Mizukawa K, Itoh T, Taniguchi M, Hosoda K, Yoshida M, Kohmura E
  • Journal Title: J Neurooncol Volume: 113(1) Issue: 1 Pages: 65-74
  • DOI: 10.1007/s11060-013-1090-x
  • Peer Reviewed
• [Journal Article] (2013)
  • Author(s): Tanaka H, Sasayama T, Tanaka K, Nakamizo S, Nishihara M, Mizukawa K, Kohta M, Koyama J, Miyake S, Taniguchi M, Hosoda K, Kohmura E
  • Journal Title: J Neurooncol Volume: 111(3) Issue: 3 Pages: 273-83
  • DOI: 10.1007/s11060-012-1027-9
  • Peer Reviewed
• [Journal Article] The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas. (2013)
  • Author(s): Gini B, Zanca C, Guo D, Matsutani T, Masui K, Ikegami S, Yang H, Nathanson D, Villa GR, Shackelford D, Zhu S, Tanaka K, Babic I, Akhavan D, Lin K, Assuncao A, Gu Y, Bonetti B, Mortensen DS, Xu S, Raymon HK, Cavenee WK, Furnari FB, James CD, Kroemer G, Heath JR, Hege K, Chopra R, Cloughesy TF, Mischel PS.
  • Journal Title: Clin Cancer Res. Volume: 19(20) Issue: 20 Pages: 5722-32
  • DOI: 10.1158/1078-0432.ccr-13-0527
  • Peer Reviewed
• [Journal Article] (2013)
  • Author(s): Ishii T, Mizukawa K, Sasayama T, Sasaki H, Hayashi S, Nakamizo S, Tanaka H, Tanaka K, Hara S, Hirai C, Itoh T, Kohmura E
  • Journal Title: Neuropathology Volume: 33(3) Issue: 3 Pages: 299-305
  • DOI: 10.1111/j.1440-1789.2012.01349.x
  • Peer Reviewed
• [Journal Article] De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients. (2013)
  • Author(s): Akhavan D, Pourzia AL, Nourian AA, Williams KJ, Nathanson D, Babic I, Villa GR, Tanaka K et al.
  • Journal Title: Cancer Discov. Volume: [Epub ahead of print]
  • Peer Reviewed
• [Journal Article] mTOR Inhibitors Synergize on Regression, Reversal of Gene Expression, and Autophagy in Hepatocellular Carcinoma. (2012)
  • Author(s): Thomas HE, Mercer CA, Carnevalli LS, Park J, Andersen JB, Conner EA, Tanaka K et al.
  • Journal Title: Sci Transl Med. Volume: 4(139) Issue: 139
  • DOI: 10.1126/scitranslmed.3003923
  • Peer Reviewed
• [Journal Article] Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240. (2012)
  • Author(s): Fenton TR, Nathanson D, Ponte de Albuquerque C, Kuga D, Iwanami A, Dang J, Yang H, Tanaka K et al.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 109(35) Issue: 35 Pages: 14164-9
  • DOI: 10.1073/pnas.1211962109
  • Peer Reviewed
• [Presentation] 天幕上low grade glioma 患者の予後規定因子について (2013)
  • Author(s): 田中一寛, 篠山隆司, 西原賢在, 水川克, 甲村英二
  • Organizer: 第72回日本脳神経外科学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Surgical management of cerebral low-grade gliomas (2013)
  • Author(s): Tanaka K, Sasayama T, Takata K, Mizukawa K, Kohmura E
  • Organizer: The 10th Annual Meeting of Asian Society for Neuro-Oncology
  • Place of Presentation: Mumbai, India
• [Presentation] 天幕上low grade glioma患者の予後規定因子について (2013)
  • Author(s): 田中一寛、篠山隆司、西原賢在、水川克、 甲村英二
  • Organizer: 第72回日本脳神経外科学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Prognostic factors for survival in patients with cerebral low-grade glioma. (2013)
  • Author(s): Tanaka K, Sasayama T, Takata K, Mizukawa K, Kohmura E
  • Organizer: The 4th Quadrennial Meeting of the World Federation of Neuro-Oncology in conjunction with the 18th Annual Meeting of the Society for Neuro-Onocology
  • Place of Presentation: San Francisco, USA
• [Presentation] mTORシグナルによる悪性グリオーマ細胞内グルタミン代謝機構の制御 (2013)
  • Author(s): 田中一寛、篠山隆司、入野康宏、甲村英二
  • Organizer: 第31回日本脳腫瘍学会
  • Place of Presentation: 宮崎
• [Presentation] Surgical management of cerebral low-grade gliomas. (2013)
  • Author(s): Tanaka K, Sasayama T, Takata K, Mizukawa K, Kohmura E
  • Organizer: 第10回アジア脳腫瘍学会
  • Place of Presentation: インド
• [Presentation] EGFレセプターの恒常的活性化によるmTORC2-NF-・B 経路の制御 (2012)
  • Author(s): 田中一寛, Paul S. Mischel, 甲村英二
  • Organizer: 第30回日本脳腫瘍学会学術集会
  • Place of Presentation: 広島
• [Presentation] Oncogenic EGFR signaling activates an mTORC2-NF-kB pathway that promotes chemotherapy resistance. (2012)
  • Author(s): Tanaka K, Mischel PS, Kohmura E
  • Organizer: 第9回アジア脳腫瘍学会
  • Place of Presentation: 台湾
• [Presentation] Oncogenic EGFR signaling activates an mTORC2-NF-kB pathway. (2012)
  • Author(s): Tanaka K, Mischel PS, Kohmura E
  • Organizer: 第30回日本脳腫瘍学会
  • Place of Presentation: 広島
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/neuro/TOP2.html