Treatment of gastrointestinal cancer by targeting the distinct energy metabolism of cancer cells

2012 Fiscal Year Final Research Report

• Project/Area Number: 23659643
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kanazawa University
• Principal Investigator: MINAMOTO Toshinari 金沢大学, がん進展制御研究所, 教授 (50239323)
• Co-Investigator(Kenkyū-buntansha): KAWAKAMI Kazuyuki 金沢大学, がん進展制御研究所, 准教授 (00293358)
• Co-Investigator(Renkei-kenkyūsha): SOGA Tomoyoshi 慶應義塾大学, 環境情報学部, 教授 (60338217)
• Project Period (FY): 2011 – 2012
• Keywords: 消化器がん / エネルギー代謝 / 標的治療 / GSK3β

Research Abstract

Recently we discovered novel pathological roles for glycogen synthase kinase-3β (GSK3β) in promoting cancer cell survival and proliferation via the modulation of cell cycle, tumor suppressor and cell immortality pathways. This has led us to propose GSK3β as a potential target for cancer treatment. A primary role for GSK3β is the control of glycogen synthase activity that switches glycogenesis and glycolysis, the two major pathways of glucose metabolism. In this research, we investigated whether GSK3β influences the aberrant glucose metabolism in gastrointestinal cancer cells. Using innovative metabolomic technology, we found a distinctive metabolic trait in cancer cells that suggests inhibition of GSK3β attenuates glycolysis (Warburg effect) and restores mitochondrial glucose oxidation.This trait could be an important molecular basis for cancer treatment targeting aberrant GSK3β.

Research Products

• [Journal Article] Aberrant glycogen synthase kinase 3β is involved in pancreatic cancer cell invasion and resistance to therapy (2013)
  • Author(s): Kitano A, Shimasaki T, Chikano Y, Nakada M, Hirose M, Higashi T, Ishigaki Y, Endo Y, Takino T, Sato H, Sai Y, Miyamoto KI, Motoo Y, Kawakami K, Minamoto T
  • Journal Title: PLoS One Volume: 8(2) Pages: e55289
  • DOI: DOI:10.1371/journal.pone
  • Peer Reviewed
• [Journal Article] Aberrant glycogen synthase kinase 3β in pancreatic cancer development, progression and resistance to therapy (2013)
  • Author(s): Shimasaki T, Kitano A, Motoo Y, Minamoto T
  • Journal Title: J Carcinog Volume: 11 Pages: 15
  • DOI: DOI:10.4103/1477-3163.100866. 査読有り
  • Peer Reviewed
• [Journal Article] LINE-1 methylation shows little intra-patient heterogeneity in primary and synchronous metastatic colorectal cancer (2012)
  • Author(s): Matsunoki A, Kawakami K, Kotake M, Kaneko M, Kitamura H, Ooi A, Watanabe G, Minamoto T
  • Journal Title: BMC Cancer Volume: 12 Pages: 574
  • DOI: DOI:10.1186/1471-2407-12-574
  • Peer Reviewed
• [Journal Article] Loss of HITS (FAM107B) expression in cancer of the multiple organs: a tissue microarray analysis (2012)
  • Author(s): Nakajima H, Koizumi K, Tanaka T, Ishigaki Y, Yoshitake Y, Yonekura H, Sakuma T, Fukushima T, Umehara H, Ueno S, Minamoto T, Motoo Y
  • Journal Title: Int J Oncol 2012 Volume: (in press)
  • DOI: DOI:10.3892/ijo.2012.1550
  • Peer Reviewed
• [Journal Article] Can population differences in chemotherapy outcomes be inferred from differences in pharmacogenetic frequencies? (2012)
  • Author(s): Loh M, Chua D, Yao Y, Soo RA, Zeps N, Platell C, Kawakami K, Minamoto T, Iacopetta B, Soong R
  • Journal Title: Pharmacogenomics J 2012 Volume: (in press)
  • DOI: DOI:10.1038/tpj.2012.26
  • Peer Reviewed
• [Journal Article] Inflammation-induced repression of tumor suppressor miR-7 in gastric epithelial cells (2012)
  • Author(s): Kong D, Piao YS, Oshima H, Oguma K, Minamoto T, Yamada Y, Sato K, Yamashita S, Ushijima T, Ishikawa T, Oshima M
  • Journal Title: Oncogene Volume: 31(35) Pages: 3949-60
  • DOI: DOI:10.1038/onc.2011.558
  • Peer Reviewed
• [Journal Article] Glycogen synthase kinase 3β inhibition sensitizes pancreatic cancer cells to gemcitabine (2012)
  • Author(s): Shimasaki T, Ishigaki Y, Nakamura Y, Takata T, Nakaya N, Nakajima H, Sato I, Zhao X, Kitano A, Kawakami K, Tanaka T, Takegami T, Tomosugi N, Minamoto T, Motoo Y
  • Journal Title: J Gastroenterol Volume: 47(3) Pages: 321-33
  • DOI: DOI:10.1007/s00535-011-0484-9
  • Peer Reviewed
• [Journal Article] AP1B plays an important role in intestinal tumorigenesis with the truncating mutation of an APC gene (2012)
  • Author(s): Mimura M, Masuda A, Nishiumi S, Kawakami K, Fujishima Y, Yoshie T, Mizun o S, Miki I, Ohno H, Hase K, Minamoto T, Azuma T, Yoshida M.
  • Journal Title: Int J Cancer Volume: 130 (5) Pages: 1011-20
  • DOI: DOI:10.1002/ijc. 26131
  • Peer Reviewed
• [Journal Article] The strategy for enhancing temozolomide against malignant glioma (2012)
  • Author(s): Nakada M, Furuta T, Hayashi Y, Minamoto T, Hamada JI
  • Journal Title: Front Oncol Volume: 2 Pages: 98
  • DOI: DOI:10.3389/fonc.2012.00098.
  • Peer Reviewed
• [Journal Article] Inhibition of gastric carcinogenesis by the hormone, gastrin, is mediated by suppression of TFF1 epigenetic silencing (2011)
  • Author(s): Tomita H, Takaishi S, Menheniott TR, Yang X, Shibata W, Jin G, Betz KS, Kawakami K, Minamoto T, Tomasetto C, Rio MC, Lerkowit N, Varro A, Giraud AS, Wang TC.
  • Journal Title: Gastroenterology Volume: 140(3) Pages: 879-91
  • DOI: DOI:10.1053/j.gastro.2010.11.037
  • Peer Reviewed
• [Journal Article] Long interspersed nuclear element-1 hypomethylation is a potential biomarker for the prediction of response to oral fluoropyrimidines in microsatellite stable and CpG island methylator phenotype-negative colorectal cancer (2011)
  • Author(s): Kawakami K, Matsunoki A, Kaneko M, Saito K, Watanabe G, Minamoto T
  • Journal Title: Cancer Sci Volume: 102(1) Pages: 166-74
  • DOI: DOI:10.1111/j.1349-7006.2010.01776.x
  • Peer Reviewed
• [Journal Article] Metabolic disorder, inflammation and deregulated molecular pathways converging in pancreatic cancer development: implications for new therapeutic strategies (2011)
  • Author(s): Motoo Y, Shimasaki T, Ishigaki Y, Nakajima H, Kawakami K, Minamoto T
  • Journal Title: Cancers Volume: 3(1) Pages: 446-60
  • DOI: DOI:10.3390/cancers3010446
  • Peer Reviewed
• [Presentation] Deregulated GSK3β sustains gastrointestinal cancer cells by modulating hTERT and telomerase (2012)
  • Author(s): Minamoto T, Mai W, Kyo S, Shakoori A, Miyashita K, Yokoi K, Shimasaki T, Motoo Y, Kawakami K
  • Organizer: 103rdAnnual Meeting of American Association for Cancer Research
  • Place of Presentation: McCormick Place, Chicago, Illinois, U.S.A.
  • Year and Date: 20120331-0404
• [Presentation] LINE-1 methylation level is a molecular marker with little intra-patient heterogeneity in primary and synchronous metastatic colorectal cancer. (2012)
  • Author(s): Matsunoki A, Kawakami K, Kotake M, KanekoM, Watanabe G, Minamoto T
  • Organizer: 103rdAnnual Meeting of American Association for Cancer Research
  • Place of Presentation: McCormick Place, Chicago, Illinois, U.S.A.
  • Year and Date: 20120331-0404
• [Presentation] がんの代謝と治療標的GSK3βの接点 (2012)
  • Author(s): 堂本貴寛,源 利成
  • Organizer: 日本癌学会シンポジウム:がんと代謝シンポジウム
  • Place of Presentation: 慶應義塾大学医学部信濃町キャンパス北里記念医学図書館講堂,東京
  • Year and Date: 20120117-18
• [Presentation] Knockdown of LINE-1 enhances sensitivity to 5-FU in LINE-1-hypomethylated colorectal cancer cell (2012)
  • Author(s): Kawakami K, Matsunoki A, Kotake M, Kaneko M, Kitamura H, Watanabe G, Minamoto T
  • Organizer: 22ndBiennial Congress of the European Association for Cancer Research
  • Place of Presentation: Centre Convencions International Barcelona, Barcelona, Spain
  • Year and Date: 2012-07-10
• [Presentation] HITS (FAM107B): novel heat-shock induced protein as a maker for cancer progression and diagnosis (2011)
  • Author(s): Nakajima H, Minamoto T, Motoo Y
  • Organizer: 16th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine
  • Place of Presentation: Hotel Rodos Palace, Rhodes Island, Greece.
  • Year and Date: 20111006-08
• [Presentation] Interleukin-1β is a signal for Trefoil factor 2 promoter methylation in gastric preneoplasia (2011)
  • Author(s): Menheniott TR, O'Connor L, Minamoto T,Kawakami K, Tomita H, Fox JG, Wan g TC,Judd LM, Giraud AS
  • Organizer: DDW 2011
  • Place of Presentation: McCormick Place, Chicago, Illinois, U.S.A.
  • Year and Date: 20110507-10
• [Book] がんのエネルギー代謝とGSK3β. 実験医学増刊 がんと代謝:何故がん細胞が好んで解糖系を使うのか? (2012)
  • Author(s): 曽我朋義,江角浩安
  • Total Pages: 48-53
  • Publisher: 羊土社
• [Book] Distinct pathologic role for glycogen synthase kinase 3β in colorectal cancer progression (2012)
  • Author(s): Minamoto T, Kotake M, Nakada M, Shimasaki T, Motoo Y, Kawakami K
  • Total Pages: 107-134
  • Publisher: InTech
• [Book] The pivotal role of GSK3β in glioma biology (2011)
  • Author(s): Nakada M, Minamoto T, Pyko IV, Hayashi Y, Hamada JI
  • Total Pages: 567-590
  • Publisher: InTech
• [Remarks]
  • URL: http://www.kanazawa-u.ac.jp/~ganken/shuyoseigyo/index.html