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Amino acid signaling in the downstream of endothelially expressed amino acid transporter LAT1 that contributes to tumor angiogenesis

Research Project

Project/Area Number 18K06931
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionOsaka University

Principal Investigator

Ohgaki Ryuichi  大阪大学, 医学系研究科, 准教授 (20467525)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsアミノ酸 / トランスポーター / LAT1 / 腫瘍血管新生 / シグナル伝達 / 血管内皮細胞 / 抗悪性腫瘍薬 / mTORC1 / 内皮細胞 / 抗腫瘍薬 / アミノ酸トランスポーター / 細胞内シグナル伝達
Outline of Final Research Achievements

We found that a cancer cell-type amino acid transporter LAT1 is highly expressed not only in cancer cells but also in tumor-associated vascular endothelium. Based on this unexpected observation, we hypothesized the functional involvement of endothelial LAT1 in tumor angiogenesis. In this study, we tried to establish LAT1 as a novel player in tumor angiogenesis and to elucidate the underlying molecular mechanisms. As a result, we showed that tumor growth can be inhibited by targeting the vascular endothelial LAT1 through the suppression of tumor blood vessel formation. We also clarified the existence of a crosstalk between the signaling of amino acids in the downstream of LAT1 and that of a major pro-angiogenic factor VEGF-A in vascular endothelial cells. This study revealed important roles of endothelial amino acid transporter and amino acid signaling in tumor angiogenesis. The obtained results hold significant implications for the development of novel anti-angiogenic therapies.

Academic Significance and Societal Importance of the Research Achievements

がん細胞へ必須アミノ酸を取込むタンパク質のアミノ酸トランスポーターLAT1は、その機能を抑制することでがんを兵糧攻めに出来ることから、新しい抗がん薬の標的として注目されている。本研究は、がん細胞以外に、がん組織内の血管を形成する内皮細胞にもLAT1が存在し、新たな血管の形成(血管新生)に寄与することを示した。また、アミノ酸と血管新生制御機構との機能的な関連性を分子レベルで示した。腫瘍内の血管は、栄養の供給や老廃物の排出を通して、がんの増殖や進展に重要な寄与をしており、現在、血管新生を抑制する抗血管新生療法が実用化されている。本研究の成果は、新しい抗血管新生療法の提唱に繋がることも期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (19 results)

All 2021 2020 2019 2018

All Journal Article (4 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (14 results) (of which Int'l Joint Research: 2 results,  Invited: 4 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Proteomics and phosphoproteomics reveal key regulators associated with cytostatic effect of amino acid transporter LAT1 inhibitor2020

    • Author(s)
      Okanishi Hiroki、Ohgaki Ryuichi、Okuda Suguru、Endou Hitoshi、Kanai Yoshikatsu
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 2 Pages: 871-883

    • DOI

      10.1111/cas.14756

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Amino acid transporter LAT1 in tumor-associated vascular endothelium promotes angiogenesis by regulating cell proliferation and VEGF-A-dependent mTORC1 activation2020

    • Author(s)
      Quan Lili、Ohgaki Ryuichi、Hara Saori、Okuda Suguru、Wei Ling、Okanishi Hiroki、Nagamori Shushi、Endou Hitoshi、Kanai Yoshikatsu
    • Journal Title

      Journal of Experimental & Clinical Cancer Research

      Volume: 39 Issue: 1 Pages: 266-266

    • DOI

      10.1186/s13046-020-01762-0

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Interaction of Halogenated Tyrosine/Phenylalanine Derivatives with Organic Anion Transporter 1 in the Renal Handling of Tumor Imaging Probes2020

    • Author(s)
      Jin Chunhuan、Wei Ling、Ohgaki Ryuichi、Tominaga Hideyuki、Xu Minhui、Okuda Suguru、Okanishi Hiroki、Kawamoto Yasuharu、He Xin、Nagamori Shushi、Kanai Yoshikatsu
    • Journal Title

      Journal of Pharmacology and Experimental Therapeutics

      Volume: 375 Issue: 3 Pages: 451-462

    • DOI

      10.1124/jpet.120.000235

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Cryo-EM structure of the human L-type amino acid transporter 1 in complex with glycoprotein CD98hc2019

    • Author(s)
      Lee Yongchan、Wiriyasermkul Pattama、Jin Chunhuan、Quan Lili、Ohgaki Ryuichi、Okuda Suguru、Kusakizako Tsukasa、Nishizawa Tomohiro、Oda Kazumasa、Ishitani Ryuichiro、Yokoyama Takeshi、Nakane Takanori、Shirouzu Mikako、Endou Hitoshi、Nagamori Shushi、Kanai Yoshikatsu、Nureki Osamu
    • Journal Title

      Nature Structural & Molecular Biology

      Volume: 26 Issue: 6 Pages: 510-517

    • DOI

      10.1038/s41594-019-0237-7

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Amino acid transporter LAT1 is upregulated in tumor-associated vascular endothelial cells and plays essential roles in tumor angiogenesis by promoting proliferation and regulating VEGF-A-dependent pro-angiogenic mTORC1 activation2021

    • Author(s)
      Ryuichi Ohgaki、Lili Quan、Suguru Okuda、Hiroki Okanishi、Shushi Nagamori、Hitoshi Endou、Yoshikatsu Kanai
    • Organizer
      第94回 日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 遊離アミノ酸量の定量的経時変化解析によるアミノ酸トランスポーター阻害効果の検討2020

    • Author(s)
      西窪 航、大垣 隆一、岡西 広樹、奥田 傑、金井 好克
    • Organizer
      第137回 日本薬理学会近畿部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Development of tumor-specific compounds avoiding renal uptake for PET imaging and targeted α-therapy2020

    • Author(s)
      Chunhuan Jin、Ling Wei、Ryuichi Ohgaki、Suguru Okuda、Minhui Xu、Hiroki Okanishi、Shushi Nagamori、Yoshikatsu Kanai
    • Organizer
      第138回 日本薬理学会近畿部会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Suppression of LAT1 in endothelial cells of tumor tissues exhibits an anti-angiogenesis effect2020

    • Author(s)
      Lili Quan, Ryuichi Ohgaki, Suguru Okuda, Shushi Nagamori, Yoshikatsu Kanai
    • Organizer
      第93回 日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Time-course analysis of the changes in intracellular amino acid concentrations and amino acid-related signaling pathways in cancer cells induced by the inhibition of cancer-type amino acid transporter LAT2020

    • Author(s)
      西窪 航、大垣 隆一、岡西 広樹、奥田 傑、金井 好克
    • Organizer
      第93回 日本薬理学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Expression of amino acid transporter LAT1 in the endothelial cells of tumor tissues and its contribution to angiogenesis2019

    • Author(s)
      Lili Quan, Ryuichi Ohgaki, Suguru Okuda, Shushi Nagamori, Yoshikatsu Kanai
    • Organizer
      第135回 日本薬理学会近畿部会
    • Related Report
      2019 Research-status Report
  • [Presentation] Identification of miRNA regulating the expression of cancer-type amino acid transporter LAT1: its potential as an antionco-miRNA2019

    • Author(s)
      劉 星明、大垣 隆一、岡西 広樹、奥田 傑、金井 好克
    • Organizer
      第136回 日本薬理学会近畿部会
    • Related Report
      2019 Research-status Report
  • [Presentation] 腫瘍間質血管内皮細胞に発現するアミノ酸トランスポーターLAT1の阻害による血管新生抑制効果2019

    • Author(s)
      全 麗麗、大垣 隆一、奥田 傑、永森 収志、遠藤 仁、金井 好克
    • Organizer
      第92回 日本薬理学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 腫瘍血管内皮細胞における必須アミノ酸 トランスポーターの発現亢進と血管新生への寄与2019

    • Author(s)
      大垣隆一
    • Organizer
      第2回 がんと代謝研究会若手の会
    • Related Report
      2018 Research-status Report
  • [Presentation] アミノ酸トランスポーターによる多様な細胞機能制御と創薬標的としての意義2019

    • Author(s)
      大垣隆一
    • Organizer
      第393回 大阪大学臨床栄養研究会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] Upregulation of an amino acid transporter LAT1 in tumour-associated blood vessels and its contribution to angiogenesis2018

    • Author(s)
      Ryuichi Ohgaki
    • Organizer
      Australia Japan Medical Research Symposium September 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] 血管内皮細胞におけるアミノ酸トランスポーターLAT1の発現と腫瘍血管新生への寄与2018

    • Author(s)
      大垣隆一
    • Organizer
      第13回 トランスポーター研究会年会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Presentation] L-type amino acid transporter 1 (LAT1) in endothelial cells of tumor vessels contributes to tumor angiogenesis2018

    • Author(s)
      Lili Quan, Ryuichi Ohgaki, Suguru Okuda, Shushi Nagamori, Yoshikatsu Kanai
    • Organizer
      18th World congress of basic and clinical pharmacology
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] アミノ酸トランスポーターを介した代謝制御と細胞機能制御2018

    • Author(s)
      大垣隆一、金井好克
    • Organizer
      第72回 日本栄養・食糧学会大会
    • Related Report
      2018 Research-status Report
    • Invited
  • [Patent(Industrial Property Rights)] がん治療剤2020

    • Inventor(s)
      金井 好克、大垣 隆一、遠藤 仁、鈴木 登紀子
    • Industrial Property Rights Holder
      ジェイファーマ株式、国立大学法人大阪大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-187983
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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