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Mechanisms of ATP-release in Cancer Cells

Research Project

Project/Area Number 18K06851
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48020:Physiology-related
Research InstitutionNagoya University

Principal Investigator

Kishio Furuya  名古屋大学, 総合保健体育科学センター, 研究員 (40132740)

Project Period (FY) 2018-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
KeywordsATP放出 / ルミネッセンスイメージング / がん微小環境 / 乳がん細胞 / S1P / VRAC / LRRC8 / xenograft / LRRC8A / 低張刺激 / DCPIB / アデノシン / 容積感受性塩素イオンチャネル / 発光イメージング
Outline of Final Research Achievements

The high interstitial ATP concentration in the tumor microenvironment (TME) is a major source of adenosine, which acts as a strong immune suppressor. However, the source of ATP release has not been elucidated. We measured ATP release during hypotonic stress using a real-time ATP imaging system in breast cell lines. We found a distinctive pattern of ATP release only in undifferentiated cells. This pattern of ATP release was suppressed by DCPIB, an inhibitor of volume-regulated anion channel (VRAC), and by the knockdown of LRRC8A, the essential molecular entity of VRAC, using shRNA. In addition, this ATP release was activated by S1P (sphingosine-1-phosphate, an inflammatory mediator in TME). In the nude mouse xenograft model, knockdown of VRAC suppressed tumorigenesis in subcutaneously implanted breast cancer cells. These results indicate that abundantly expressed VRAC is a conduit of ATP release in undifferentiated cells including cancer cells and progress tumorigenesis in vivo.

Academic Significance and Societal Importance of the Research Achievements

がんは自らの周りに生存を維持するための微小環境を構築しており、そこにはATPが高濃度で存在する。このATPの一つの大きな役割は分解によりアデノシンを生成、高濃度に維持することにより、がんに対する免疫攻撃を抑制することである。しかしがん微小環境においてATPが高濃度に維持されるメカニズムは分かっていなかった。本研究はがん細胞特異的なATP放出機序としてVRACの関与を示した。またヌードマウスのxenograftモデルを用い実際VRACががん組織の成長に必要なことを明らかにした。このATPシグナリング系はがん抑制の免疫系と関連しており免疫治療の効き方を左右する1つのシーズとして提唱できる。

Report

(7 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (13 results)

All 2022 2021 2020 2019 2018

All Journal Article (7 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 5 results,  Open Access: 6 results) Presentation (6 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Sphingosine-1-Phosphate Induces ATP Release via Volume-Regulated Anion Channels in Breast Cell Lines2022

    • Author(s)
      Furuya K, Takahashi Y, Hirata H, Kobayashi T, Sokabe M
    • Journal Title

      J Physiol Sci

      Volume: 72 (suppl 1) Pages: 109-109

    • DOI

      10.1186/s12576-022-00851-3

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sphingosine-1-Phosphate Induces ATP Release via Volume-Regulated Anion Channels in Breast Cell Lines2021

    • Author(s)
      Furuya K, Hirata H, Kobayashi T, Sokabe M
    • Journal Title

      Life

      Volume: 11 Issue: 8 Pages: 851-851

    • DOI

      10.3390/life11080851

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hypo-osmotic Stress Induces ATP Release via Volume-regulated Anion Channels in Undifferentiated Mammary Cells2021

    • Author(s)
      Furuya K, Takahashi Y, Hirata H, Kobayashi T, Samsonov M, Sokabe M
    • Journal Title

      bioRxiv

      Volume: April 26

    • DOI

      10.1101/2021.04.25.441329

    • Related Report
      2021 Research-status Report
    • Open Access
  • [Journal Article] Lytic Release of Cellular ATP: Physiological Relevance and Therapeutic Applications2021

    • Author(s)
      Grygorczyk R, Boudreault F, Ponomarchuk O, Tan JJ, Furuya K, Goldgewicht J, Kenfack FD, Yu F
    • Journal Title

      Life

      Volume: 11 Issue: 7 Pages: 700-700

    • DOI

      10.3390/life11070700

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inflation of ex-vivo Rat Lung in Negative Pressure Chamber Induced ATP Release in Alveoli and Surrounding Blood Capillary2020

    • Author(s)
      Furuya K, Tan J, Grygorczyk R, Sokabe M
    • Journal Title

      J Physiol Sci

      Volume: 70

    • Related Report
      2020 Research-status Report
  • [Journal Article] Mechanosensitive ATP release in the lungs: New insights from real-time luminescence imaging studies.2019

    • Author(s)
      Grygorczyk Ryszard、Boudreault Francis、Tan Ju Jing、Ponomarchuk Olga、Sokabe Masahiro、Furuya Kishio
    • Journal Title

      Current Topics in Membranes

      Volume: 83 Pages: 45-76

    • DOI

      10.1016/bs.ctm.2019.02.001

    • ISBN
      9780128177648
    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cyclic stretch enhances reorientation and differentiation of 3-D culture model of human airway smooth muscle2018

    • Author(s)
      Asano Shuichi、Ito Satoru、Morosawa Mika、Furuya Kishio、Naruse Keiji、Sokabe Masahiro、Yamaguchi Etsuro、Hasegawa Yoshinori
    • Journal Title

      Biochemistry and Biophysics Reports

      Volume: 16 Pages: 32-38

    • DOI

      10.1016/j.bbrep.2018.09.003

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] フィンゴシン-1-フォスフェートは未分化乳腺上皮株細胞において容積感受性アニオンチャネルを介したATP放出を引き起こす2021

    • Author(s)
      古家 喜四夫, 高橋 優子, 平田 宏聡, 小林 剛, 曽我部 正博
    • Organizer
      第99回日本生理学会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 容量感受性陰イオンチャネル(VRAC)を介した未分化乳腺上皮細胞におけるATP放出2021

    • Author(s)
      古家 喜四夫, 高橋 優子, 平田 宏聡, 小林 剛, 曽我部 正博
    • Organizer
      第98回日本生理学会大会
    • Related Report
      2020 Research-status Report
  • [Presentation] 陰圧チェンバーを用いたラット摘出肺の膨張刺激は肺腺胞内および周りの毛細血管にATP放出を引き起こす2020

    • Author(s)
      古家喜四夫、Ju Jing Tan, Ryszard Grygorczyk、曽我部正博
    • Organizer
      第97回日本生理学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Mechanisms of Inflation-Induced ATP Release in Ex Vivo Rat Lungs: A Bioluminescence Imaging Study2019

    • Author(s)
      Tan J, Furuya K, Boudreault F, Brochiero E, Grygorczyk R
    • Organizer
      American Thoracic Society International Conference (ATS) 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Hypotonic Stress Induces ATP Release via Volume-regulated Anion Channels in Breast Cell Lines2019

    • Author(s)
      Furuya K, Takahashi Y, Sokabe M
    • Organizer
      9th FAOPS and The 96th Annual Meeting of the Physiological Society of Japan
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Hypotonic Stress Induced-ATP Release is via Volume-regulated Anion Channels in Undifferentiated Breast Cell Lines2018

    • Author(s)
      Furuya K, Takahashi Y, Sokabe M
    • Organizer
      Asian Biophysics Association Symposium
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2025-01-30  

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