Development of novel glycan-based drug for cancer, COPD and Alzheimer's disease

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15H04700
• Research Institution: Osaka International Cancer Institute
• Principal Investigator: 谷口 直之 地方独立行政法人大阪府立病院機構大阪国際がんセンター(研究所), その他部局等, 糖鎖オンコロジー部部長 (90002188)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 糖鎖 / 糖転移酵素 / COPD / アルツハイマー病 / がん / レドックス

Outline of Annual Research Achievements

本研究では、糖鎖が発症や進展に深く関与するがん、アルツハイマー病、慢性閉塞性肺疾患(COPD)に焦点を絞り、病態形成過程で糖鎖の発現・機能がどう破綻するのかを明らかにし、糖鎖を標的にした新たな創薬研究の展開を目的としている。
平成29-30年度の研究で、がんと深く関わるフコシル化糖鎖の生合成を阻害する新たな糖アナログを開発した。本化合物を肝がん細胞に添加したところ、がんの浸潤が抑制されることがわかった(Kizuka et al., Cell Chem. Biol)。また、がんの転移を助長する糖鎖の合成酵素としてよく知られるGnT-Vの立体構造を明らかにした(Nagae et al., Nat. Commun.)。
アルツハイマー病を促進する糖鎖の合成酵素として代表者らが発見したGnT-IIIについては、現在阻害剤の探索をハイスループットスクリーニングによって行なっている。
COPD研究については、抗炎症効果を通じて肺気腫抑制効果を示すことを明らかにしたL4糖鎖について、化学的な多量体化を行なった。多量体L4は、受容体候補と考えられるLangerinとの親和性がL4モノマーの1000倍以上に高まり、in vivoにおける抗炎症効果も高いことがわかった(Ota et al., Biochim. Biophys. Acta)。現在、L4のさらなる化学修飾、L4の作用メカニズムの探索などを行なっている。また、COPDや関連する肺疾患患者の血清の糖鎖解析を行なっており、これら肺疾患に応じて発現が変動する糖タンパク質糖鎖を見出した。現在この解析を進めている。
さらに、以上の研究成果の一部を総説論文として、Cell. Immunol. 誌、Glycoconj. J. 誌、Biochim. Biophys. Actaに発表している。

Research Progress Status

平成29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Implication of C-type lectin receptor langerin and keratan sulfate disaccharide in emphysema. (2018)
  • Author(s): Kizuka y, Mishra S, Yamaguchi Y, Taniguchi N
  • Journal Title: Cell Immunol. Volume: 333 Pages: 80-84
  • DOI: 10.1016/j.cellimm.2018.07.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neural functions of bisecting GlcNAc. (2018)
  • Author(s): Kizuka Y, Taniguchi N
  • Journal Title: Glycoconj. J. Volume: ー Pages: ー
  • DOI: 10.1007/s10719-018-9829-4.
  • Peer Reviewed
• [Journal Article] High affinicty sugar ligands of C-type lectin receptor langerin. (2018)
  • Author(s): Ota F, Hirayama T, Kizuka Y, Yamaguchi y, Fujinawa R, Nagata M, Ismanto HS, Lepenies B, Aretz J, Rademacher C, Seeberger RH, Angata T, Kitazume S, Yoshida K, Betsuyaku T, Kida K, Yamasaki S, Taniguchi N
  • Journal Title: Biochim Biophys Acta Gen Subj. Volume: 1862 Pages: 1592-1601
  • DOI: 10.1016/j.bbagen.2018.04.004.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Glycosylation controls cooperative PECAM-VEGFR2-β3 integrin functions at the endothelial surface for tumor angiogenesis. (2018)
  • Author(s): Imamaki R, Ogawa K, Kizuka Y, Komi Y, Kotani N, Honke K, Honda T, Taniguchi N, Kitazume S
  • Journal Title: Oncogene Volume: 37(31) Pages: 4287-4299
  • DOI: 10.1038/s41388-018-0271-7.
  • Peer Reviewed
• [Journal Article] Metabolic control of T cell immune response through glycans in inflammatory bowel disease. (2018)
  • Author(s): Dias AM, Correia A, Pereira MS, Almeida CR, Alves I, Pinto V, Catarino TA, Mendes S, Leander M, Oliva-Teles MT, Maia L, Delerue-Matos C, Taniguchi N, Lima M, Pedroto I, Marcos-Pinto R, Lago P, Reis CA, Vilanova M, Pinho SS
  • Journal Title: Proc Natl Acad Sci U S A Volume: 115(20) Pages: E4651-E4660
  • DOI: 10.1073/pnas.1720409115.
  • Peer Reviewed / Open Access
• [Journal Article] Structure and mechanism of cancer-associated N-acetylglucosaminyltransferase-V. (2018)
  • Author(s): Nagae M, Kizuka Y, Mihara E, Kitago Y, Hanashima S, Ito Y, Takagi J, Taniguchi N, Yamaguchi Y
  • Journal Title: Nat Commun Volume: 9 Pages: 3380
  • DOI: 10.1038/s41467-018-05931-w.
  • Peer Reviewed / Open Access
• [Journal Article] Core fucose is essential glycosylation for CD14-dependent Toll-like receptor 4 and Toll-like receptor 2 signaling in macrophages. (2018)
  • Author(s): Nakayama K, Wakamatsu K, Fujii H, Shinzaki S, Takamatsu S, Kitazume S, Kamada Y, Takehara T, Taniguchi N, Miyoshi E
  • Journal Title: J Biochem Volume: ー Pages: ー
  • DOI: 10.1093/jb/mvy098.
  • Peer Reviewed
• [Journal Article] Generation of the heterogeneity of extracelluar vesicles by membrane organization and sortin machineries. (2018)
  • Author(s): Harada Y, Suzuki T, Fukushige T, Kizuka Y, Yagi H, Yamamoto M, Kondo K, Inoue H, Kato K, Taniguchi N, Kanekura T, Dohmae N, Maruyama I
  • Journal Title: Biochim Biophys Acta Gen Subj. Volume: 1863 Pages: 681-691
  • DOI: 10.1016/j.bbagen.2019.01.015
  • Peer Reviewed
• [Journal Article] Core Fucosylation of the T cell receptor is required for T cell activation (2018)
  • Author(s): Liang W, Mao S, Sun S, Li M, Li Z, Yu R, Ma T, Gu J, Zhang J, Taniguchi N, Li W,
  • Journal Title: Front Immunol., Volume: 9 Pages: 78
  • DOI: 10.3389/fimmu.2018.00078.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification and characterization of UDP-mannose in human cell lines and mouse organs: Differential distribution across brain regions and organs. (2018)
  • Author(s): Nakajima K, Kizuka Y, Yamaguchi Y, Hirabayashi Y, Takahashi K, Yuzawa Y, Taniguchi N,
  • Journal Title: Biochem Biophys Res Commun., Volume: 495(1) Pages: 401-407
  • DOI: 10.1016/j.bbrc.2017.10.173.
  • Peer Reviewed
• [Journal Article] Sialylation of extracellular superoxide dismutase (EC-SOD) enhances furin-mediated cleavage and secretion. (2017)
  • Author(s): Ota F, Kizuka Y, Nakano M, Yamaguchi Y, Kitazume S, Ookawara T, Taniguchi N
  • Journal Title: Glycobiology Volume: 27(12) Pages: 1081-1088
  • DOI: 10.1093/glycob/cwx087
  • Peer Reviewed / Open Access
• [Journal Article] An Alkynyl-fucose Halts Hepatoma Cell Migration and Invasion by Inhibiting GDP-Fucose Synthesizing Enzyme FX, TSTA3. (2017)
  • Author(s): Kizuka Y, Nakano M, Yamaguchi Y, Nakajima K, Oka R, Sato K, Hsu TL, Wong CH, Taniguchi N.
  • Journal Title: Cell chemical biology Volume: 24(12) Pages: 1467-1478
  • DOI: 10.1016/j.chembiol.2017.08.023.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Core fucose is critical for CD14-dependent Toll-like receptor 4 signaling (2017)
  • Author(s): Iijima J, Kobayashi S, Kitazume S, Kizuka Y, Fujinawa R, Korekane H, Shibata T, Saitoh S, Akashi-Takamura S, Miyake K, Miyoshi E, Taniguchi N
  • Journal Title: Glycobiology Volume: 27(11) Pages: 1006-1015
  • DOI: 10.1093/glycob/cwx075.
  • Peer Reviewed / Open Access
• [Journal Article] Effect of spermine-derived AGEs on oxidative stress and polyamine metabolism. (2017)
  • Author(s): Tsutsui A, Pradipta AR, Kitazume S, Taniguchi N, Tanaka K.
  • Journal Title: Organic & Biomolecular Chemistry Volume: 15(32) Pages: 6720-6724
  • DOI: 10.1039/c7ob01346a.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] In-situ ligation of high- and low-affinity ligands to cell surface receptors enables highly selective recognition. (2017)
  • Author(s): Taichi M, Nomura S, Nakase I, Imamaki R, Kizuka Y, Ota F, Dohmae N, Kitazume S, Taniguchi N, Tanaka K.
  • Journal Title: Advanced science (Weinheim, Baden-Wurttemberg, Germany) Volume: 4(11) Pages: 1700147
  • DOI: 10.1002/advs.201700147
  • Peer Reviewed / Open Access
• [Journal Article] Influence of SIGLEC9 polymorphisms on COPD phenotypes including exacerbation frequency. (2017)
  • Author(s): Ishii T, Angata T, Wan ES, Cho MH, Motegi T, Gao C, Ohtsubo K, Kitazume S, Gemma A, ParE PD, Lomas DA, Silverman EK, Taniguchi N, Kida K.
  • Journal Title: Respirology Volume: 22(4) Pages: 684-690
  • DOI: 10.1111/resp.12952.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer cell targeting driven by selective polyamine reactivity with glycine propargyl esters. (2017)
  • Author(s): Vong KKH, Tsubokura K, Nakao Y, Tanei T, Noguchi S, Kitazume S, Taniguchi N, Tanaka K.
  • Journal Title: Chemical Communications Volume: 53(60) Pages: 8403-8406
  • DOI: 10.1039/c7cc01934c.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Reactivity of anti-HNK-1 antibodies to branched O-mannose glycans associated with demyelination. (2017)
  • Author(s): Sakuda K, Kizuka Y, Yamaguchi Y, Tanaka K, Ogiwara K, Segawa T, Hagiwara Y, Matsuo I, Ogawa H, Taniguchi N, Kitazume S.
  • Journal Title: Biochemical and biophysical research communications Volume: 487(2) Pages: 450-456
  • DOI: 10.1016/j.bbrc.2017.04.085.
  • Peer Reviewed
• [Journal Article] Alteration of N-glycan expression profile and glycan pattern of glycoproteins in human hepatoma cells after HCV infection. (2017)
  • Author(s): Xiang T, Yang G, Liu X, Zhou Y, Fu Z, Lu F, Gu J, Taniguchi N, Tan Z, Chen X, Xie Y, Guan F, Zhang XL.
  • Journal Title: Biochimica et biophysica acta. General subjects Volume: 1861(5Pt A) Pages: 1036-1045
  • DOI: 10.1016/j.bbagen.2017.02.014.
• [Journal Article] Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene. (2017)
  • Author(s): Fujihira H, Masahara-Negishi Y, Tamura M, Huang C, Harada Y, Wakana S, Takakura D, Kawasaki N, Taniguchi N, Kondoh G, Yamashita T, Funakoshi Y, Suzuki T.
  • Journal Title: PLoS genetics Volume: 13(4) Pages: e100696
  • DOI: 10.1371/journal.pgen.1006696.
  • Open Access
• [Presentation] グルタチオン研究からシステム糖鎖生物学へ Old sake in a new bottle (2018)
  • Author(s): 谷口直之
  • Organizer: 日本NO学会日本酸化ストレス学会
• [Presentation] 糖鎖研究の目指すもの (2018)
  • Author(s): 谷口直之
  • Organizer: 第６５回日本生化学会近畿支部例会
• [Presentation] Systems Glycobiology in Disease and N-glycan Branching (2018)
  • Author(s): Naoyuki Taniguchi
  • Organizer: 24th IUBMB Congress & 15th FAOBMB Congress 2018
  • Int'l Joint Research
• [Presentation] Branching N-glycans in disease: biomarker discovery and therapeutic approach (2018)
  • Author(s): Naoyuki Taniguchi
  • Organizer: The 11th International Symposium on Glycosyltransferases (GlycoT 2018)
  • Int'l Joint Research
• [Presentation] Glycosyltransferases: Structure and Function (2018)
  • Author(s): Naoyuki Taniguchi
  • Organizer: The 11th International Symposium on Glycosyltransferases (GlycoT 2018)
  • Int'l Joint Research
• [Presentation] 糖鎖研究の目指すもの (2018)
  • Author(s): 谷口直之
  • Organizer: オリエンタル酵母長浜研究所研究会
• [Presentation] A unique N-glycan structure, bisecting GlcNAc and Alzheimer's disease (2018)
  • Author(s): Naoyuki Taniguchi
  • Organizer: 15th Meeting of the Asian-Pacific Society for Neurochemistry
  • Int'l Joint Research
• [Presentation] Sugar chains (Glycans) and Cancer (2018)
  • Author(s): 谷口直之
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 糖鎖と病気の発症、診断、治療 (2018)
  • Author(s): 谷口直之
  • Organizer: 山口大学医学部講義
• [Presentation] コレクチンと補体系について（若宮信隆） (2018)
  • Author(s): 谷口直之
  • Organizer: 第28回日本メイラード学会年会
• [Presentation] Outline o Two-Year Strategic Plan for the HPP (2018)
  • Author(s): Naoyuki Taniguchi
  • Organizer: HUPO 2018
  • Int'l Joint Research
• [Presentation] Nutrient Regulation of Signaling and Here Expression by O-GIcNAc (Gerald W.Hart) (2018)
  • Author(s): 谷口直之
  • Organizer: 第16回糖鎖科学コンソーシアムシンポジウム
• [Presentation] Branching N-glycans and disease: approach from biochemistry to systems glycobiology (2018)
  • Author(s): Naoyuki Taniguchi
  • Organizer: 2018 Annual Meeting of the Society for Glycobiology
  • Int'l Joint Research
• [Presentation] Branching N-glycans in disease onset, biomarker discovery and therapeutics (2018)
  • Author(s): Naoyuki Taniguchi
  • Organizer: 1st Academic Seminar of IPRC & IGRC
  • Int'l Joint Research / Invited
• [Book] Glycoscience: Basic Science to Applications - Insights from the Japan Consortium for Glycobiology and Glycotechnology - (2019)
  • Author(s): Taniguchi N, Endo T, Hirabayashi J, Nishihara S, Kadomatsu K, Akiyoshi K, Aoki-Kinoshita KF, eds.
  • Total Pages: 337
  • Publisher: Springer Singapore
  • ISBN: 9789811358555
• [Book] ベインズ・ドミニチャク生化学（原書4版） (2018)
  • Author(s): Baynes John W., Dominiczak Marek H, 谷口 直之, 岩井 一宏, 藤井 順逸, 本家 孝一 (担当:共著)
  • Total Pages: 728
  • Publisher: エルゼビア・ジャパン, 丸善出版 (発売)
  • ISBN: 9784621301692