Screening of PECAM antagonist having anti-tumor angiogenesis

• Project/Area Number: 16K08601
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Kitazume Shinobu 国立研究開発法人理化学研究所, 脳神経科学研究センター, 客員研究員 (80301753)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 腫瘍血管新生 / シアル酸 / PECAM / インテグリン / VEGFR2 / アポトーシス / α2,6-シアル酸 / ST6Gal I / 血管内皮細胞 / 糖鎖 / ＶＥＧＦＲ２ / 化合物アレイ / 血管内内皮細胞 / 血管新生 / アンタゴニスト

Outline of Final Research Achievements

We found that ST6Gal I KO mice, which lack a2,6-sialic acid, exhibit retarded tumor growth due to impaired tumor angiogenesis. Actualy ST6Gal I KO endothelial cells exhibited a reduction in the cell surface residency of platelet endothelial cell adhesion molecule (PECAM). In this study, we found that in ST6Gal I KO cells, cell surface PECAM-VEGFR2 complexes were lost, and both VEGFR2 internalization and the VEGFR-dependent signaling pathway were enhanced. Second, enhanced anoikis was observed, suggesting that theabsence of α2,6-sialic acid leads to dysregulated integrin signaling. Taken together, acid, leading to abnormal signal transduction, resulting in enhanced endothelial apoptosis. Endothelial α2,6-sialylation could be a novel target for antiangiogenesis
therapy.

Academic Significance and Societal Importance of the Research Achievements

血管内皮細胞におけるα2,6-シアル酸は、新規の抗血管新生阻害剤標的となり得ることが本研究から明らかになりました。α2,6-シアル酸欠損マウスは免疫系の軽微な異常が見られるため、阻害剤は免疫系の副作用をもたらす可能性があります。現在、α2,6-シアル酸を模倣した低分子化合物のスクリーニング中であり、将来的にPECAMの相互的結合を阻害するような選択的化合物を得られれば、新たな抗血管新生阻害剤の候補になると期待できます。

Research Products

• [Journal Article] Glycosylation controls cooperative PECAM-VEGFR2-β3 integrin functions at the endothelial surface for tumor angiogenesis. (2018)
  • Author(s): 1.Imamaki R. Ogawa K, Kizuka Y, Komi Y, Kojima S, Kotani N, Honke K, Honda T, Taniguchi N, and Kitazume S*.
  • Journal Title: Oncogene Volume: 37 Pages: 4287-4299
  • Peer Reviewed / Open Access
• [Journal Article] CD22-binding synthetic sialosides regulate B lymphocyte proliferation through CD22 ligand-dependent and independent pathways, and enhances antibody production in mice (2018)
  • Author(s): 2.Matsubara N, Imamura A, Yonemiz Tu, Akatsu C, Yang H, Ueki A, Watanabe N, Abdu-Allah H, Numoto N, Takematsu H, Kitazume S, Tedder FT, Marth JD, Ito N, Ando H, Ishida H, Kiso M, and Tsubata T
  • Journal Title: Frontiers in Immunology Volume: - Pages: 820-820
  • DOI: 10.3389/fimmu.2018.00820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High affinity 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, Aretz J, Rademacher C, Seeberger PH; Angata T, Kitazume S, Yoshida K, Betsuyaku T, Kida K Yamasaki S, and Taniguchi N
  • Journal Title: BBA - General Subjects Volume: - Issue: 7 Pages: 1592-1601
  • DOI: 10.1016/j.bbagen.2018.04.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 1.Imamaki R. Ogawa K, Kizuka Y, Komi Y, Kojima S, Kotani N, Honke K, Honda T, Taniguchi N, and Kitazume S (2018)
  • Author(s): 1.Imamaki R. Ogawa K, Kizuka Y, Komi Y, Kojima S, Kotani N, Honke K, Honda T, Taniguchi N, and Kitazume S
  • Journal Title: Oncogene Volume: - Issue: 31 Pages: 4287-4299
  • DOI: 10.1038/s41388-018-0271-7
  • Peer Reviewed / Open Access
• [Journal Article] Core fucose is critical for CD14-dependent Toll-like receptor 4 signaling (2017)
  • Author(s): 4.Iijima J, Kobayashi S, Kitazume S*, Kizuka Y, Fujinawa R, Korekane H, Shibata T, Saitoh S, Akashi-Takamura S, Miyake K, Miyoshi E, and Taniguch N
  • Journal Title: Glycobiology Volume: 2017 Issue: 11 Pages: 1006-1015
  • DOI: 10.1093/glycob/cwx075
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory Role of α2,6-Sialylation in Adipogenesis. (2017)
  • Author(s): Kaburagi T, Kizuka Y, Kitazume S, and Taniguchi N.
  • Journal Title: J. Biol. Chem Volume: -
  • Peer Reviewed / Open Access
• [Journal Article] PECAM (2017)
  • Author(s): Kitazume S
  • Journal Title: Encyclopedia in Signaling Molecules Volume: -
• [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, and Kitazume S
  • Journal Title: BBRC Volume: 487 Pages: 450-456
  • Peer Reviewed
• [Presentation] Endothelial O-GalNAc glycosylation pathway determines APP processing for vascular Aβ deposition (2017)
  • Author(s): Kitazume S
  • Organizer: AD/PD2016
  • Place of Presentation: ウイーン（オーストリア）
  • Year and Date: 2017-03-30
  • Int'l Joint Research
• [Presentation] Endothelial glycan is an attractive therapeutic target (2017)
  • Author(s): Kitazume S
  • Organizer: RIKEN International symposium Systems Glycobiology and Beyond
  • Int'l Joint Research / Invited
• [Presentation] How glycosylation affects amyloid beta production? (2017)
  • Author(s): Kitazume S
  • Organizer: Glyconeuro 1st
  • Int'l Joint Research / Invited
• [Presentation] アルツハイマー病態をコントロールする糖鎖修飾 (2017)
  • Author(s): 爪しのぶ
  • Organizer: ConBio2017
  • Invited
• [Presentation] アミロイド産生と脳アミロイド アンギオパチーを規定する 血管内皮細胞のO-GalNAc型糖鎖 (2016)
  • Author(s): 北爪しのぶ
  • Organizer: 第35回日本糖質学会
  • Place of Presentation: 高知市文化プラザ(高知県・高知市)
  • Int'l Joint Research
• [Book] 生体の科学 (2016)
  • Author(s): 北爪しのぶ
  • Total Pages: 11
  • Publisher: 医学書院
• [Remarks]
  • URL: http://www.fmu.ac.jp/univ/kenkyuseika/research/180510.html
• [Remarks]
  • URL: http://www.riken.jp/pr/press/2018/20180510_1/
• [Patent(Industrial Property Rights)] 多発性硬化症マーカー (2018)
  • Inventor(s): 北爪しのぶ、作田香子、谷口直之、橋本康弘、本多たかし、斎藤清
  • Industrial Property Rights Holder: 北爪しのぶ、作田香子、谷口直之、橋本康弘、本多たかし、斎藤清
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-028329
  • Filing Date: 2018
• [Patent(Industrial Property Rights)] 認知症診断の為の可溶型アミロイドβ前駆体タンパク質７７０β切断産物の検出方法 (2016)
  • Inventor(s): 北爪しのぶ、谷口直之、立田由里子、西道隆臣、橋本康弘、本多たかし
  • Industrial Property Rights Holder: 北爪しのぶ、谷口直之、立田由里子、西道隆臣、橋本康弘、本多たかし
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-04-22
  • Acquisition Date: 2017-01-22