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Elucidation of novel functions of VCP, a major ATPase in the cell

Research Project

Project/Area Number 19H03435
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionKyoto University

Principal Investigator

KAKIZUKA Akira  京都大学, 生命科学研究科, 教授 (80204329)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2019: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
KeywordsVCP / 飢餓 / 前立腺癌 / フェロトーシス / 生体応答 / VCP/p97 / 前立腺細胞 / GSH / VCP・p97 / 前立性癌 / 新規機能 / 細胞保護 / p97/VCP
Outline of Research at the Start

ヒトは一日あたりその体重に相当する重さのATPの合成と分解を行っていると言われており、ATPとATPaseは、生物(細胞)の活動になくてはならないものである。可溶性ATPaseの中で最も豊富に存在するのがVCPである。本研究では、VCPが果たす細胞・生体での役割の内、VCPによって栄養源が感知されるメカニズムとそのメカニズムが破綻したときに引き起こされる新たな細胞死のメカニズムの解明を目的とする。

Outline of Final Research Achievements

Organisms respond to environmental changes and maintain homeostasis in them. Starvation is a representative of the environmental changes we encounter on a daily basis. We have assumed that VCP, the most abundant soluble ATPase in cells, is a key molecule that controls intracellular energy production and consumption. In this study, we showed that there is a previously unknown mechanism that protects cells from starvation: when PC3 and other prostate cancer cells are starved, VCP senses a decrease in glutamine and changes its localization to aggregate-like structures, thereby reducing the amount of free VCP, then suppressing mitochondrial activities, and inhibiting ROS production, and the resulting ferroptosis (cell death). In addition, we found that KUS121, a compound that specifically inhibits the ATPase activity of VCP, can dramatically improve the pathological conditions of renal reperfusion models and traumatic knee arthropathy models.

Academic Significance and Societal Importance of the Research Achievements

生物の生存にとって最大の脅威の1つが飢餓であるが、飢餓に対して生物がどのような対応を行っているかはよく解っていなかった。本研究によって、細胞内でエネルギー代謝を制御する鍵分子であるVCPと呼ばれる主要なATPaseが、飢餓時に細胞内で凝集体様の構造物に局在を変化させることで、フェロトーシスとよばれる急激な細胞死を回避するメカニズムが存在することを明らかにした。一方、急性の腎傷害、膝関節症モデルに対し、このVCPのATPase活性を特異的に抑制する薬剤(KUS121)の投与が、有効な治療に繋がる可能性を動物実験で示すことができた。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (21 results)

All 2022 2021 2020 2019 Other

All Journal Article (15 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 15 results,  Open Access: 15 results) Presentation (2 results) (of which Invited: 2 results) Remarks (2 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] A Novel VCP modulator KUS121 exerts renoprotective effects in ischemia-reperfusion injury with retaining ATP and restoring ERAD-processing capacity.2022

    • Author(s)
      Hata Yusuke、Date Ryosuke、Fujimoto Daisuke、Ikeda Hanako Ohashi、Umemoto Shuro、Kanki Tomoko、Nishiguchi Yoshihiko、Mizumoto Teruhiko、Hayata Manabu、Kakizoe Yutaka、Izumi Yuichiro、Kakizuka Akira、Mukoyama Masashi、Kuwabara Takashige
    • Journal Title

      American Journal of Physiology-Renal Physiology

      Volume: - Issue: 5 Pages: F577-F586

    • DOI

      10.1152/ajprenal.00392.2021

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] KUS121 attenuates the progression of monosodium iodoacetate-induced osteoarthritis in rats2021

    • Author(s)
      Iwai Sachiko、Ikeda Hanako O.、Mera Hisashi、Nishitani Kohei、Saito Motoo、Tsujikawa Akitaka、Kakizuka Akira
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 15651-15651

    • DOI

      10.1038/s41598-021-95173-6

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] VCP relocalization limits mitochondrial activity, GSH depletion and ferroptosis during starvation in PC3 prostate cancer cells.2021

    • Author(s)
      Ogor P, Yoshida T, Koike M, Kakizuka A.
    • Journal Title

      Genes Cells

      Volume: 26 Issue: 8 Pages: 570-582

    • DOI

      10.1111/gtc.12872

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hop flower extracts mitigate retinal ganglion cell degeneration in a glaucoma mouse model2020

    • Author(s)
      Hasegawa Tomoko、Ikeda Hanako O.、Iwai Sachiko、Sasaoka Norio、Kakizuka Akira、Tsujikawa Akitaka
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 21653-21653

    • DOI

      10.1038/s41598-020-78731-2

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis.2020

    • Author(s)
      Saito M, Nishitani K, Ikeda HO, Yoshida S, Iwai S, Ji X, Nakahata A, Ito A, Nakamura S, Kuriyama S, Yoshitomi H, Murata K, Aoyama T, Ito H, Kuroki H, Kakizuka A, Matsuda S.
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 20787-20787

    • DOI

      10.1038/s41598-020-77735-2

    • NAID

      120006940250

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Single-cell dynamics of pannexin-1-facilitated programmed ATP loss during apoptosis2020

    • Author(s)
      Imamura Hiromi、Sakamoto Shuichiro、Yoshida Tomoki、Matsui Yusuke、Penuela Silvia、Laird Dale W、Mizukami Shin、Kikuchi Kazuya、Kakizuka Akira
    • Journal Title

      eLife

      Volume: 9

    • DOI

      10.7554/elife.61960

    • NAID

      120006893984

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetic screening for potassium channel mutations in Japanese autosomal dominant spinocerebellar ataxia2020

    • Author(s)
      Tada Yui、Kume Kodai、Matsuda Yukiko、Kurashige Takashi、Kanaya Yuhei、Ohsawa Ryosuke、Morino Hiroyuki、Tabu Hayato、Kaneko Satoshi、Suenaga Toshihiko、Kakizuka Akira、Kawakami Hideshi
    • Journal Title

      Journal of Human Genetics

      Volume: 65(4) Issue: 4 Pages: 363-369

    • DOI

      10.1038/s10038-019-0717-y

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of VCP modulators on gene expression profiles of retinal ganglion cells in an acute injury mouse model2020

    • Author(s)
      Hasegawa Tomoko、Ikeda Hanako Ohashi、Gotoh Norimoto、Iida Kei、Iwai Sachiko、Nakano Noriko、Kakizuka Akira、Tsujikawa Akitaka
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 4251-4251

    • DOI

      10.1038/s41598-020-61160-6

    • NAID

      120006870291

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Safety and Effectiveness of a Novel Neuroprotectant, KUS121, in Patients With Non-Arteritic Central Retinal Artery Occlusion: An Open-Label, Non-Randomized, First-In-Humans, Phase 1/2 Trial2020

    • Author(s)
      Ikeda HO, Muraoka Y, Hata M, Sumi E, Ikeda T, Nakagawa T, Abe H, Tada H, Morita S, Kakizuka A, Yoshimura N, Tsujikawa A
    • Journal Title

      Plos ONE

      Volume: 15 Issue: 2 Pages: e0229068-e0229068

    • DOI

      10.1371/journal.pone.0229068

    • NAID

      120006799242

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] OLIVe: A Genetically Encoded Fluorescent Biosensor for Quantitative Imaging of Branched-Chain Amino Acid Levels inside Single Living Cells2019

    • Author(s)
      Yoshida Tomoki、Nakajima Hitomi、Takahashi Sena、Kakizuka Akira、Imamura Hiromi
    • Journal Title

      ACS Sensors

      Volume: 4 Issue: 12 Pages: 3333-3342

    • DOI

      10.1021/acssensors.9b02067

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E2 synthesis in the brain and their behavioral relevance2019

    • Author(s)
      Nie Xiang、Kitaoka Shiho、Shinohara Masakazu、Kakizuka Akira、Narumiya Shuh、Furuyashiki Tomoyuki
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 17548-17548

    • DOI

      10.1038/s41598-019-54082-5

    • NAID

      120006996939

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cardioprotective Effects of VCP?Modulator KUS121 in Murine and Porcine Models of Myocardial Infarction2019

    • Author(s)
      Ide Yuya, at al.
    • Journal Title

      JACC: Basic to Translational Science

      Volume: 4 Issue: 6 Pages: 701-714

    • DOI

      10.1016/j.jacbts.2019.06.001

    • NAID

      120006734885

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ellagic acid, extracted from Sanguisorba officinalis, induces G1 arrest by modulating PTEN activity in B16F10 melanoma cells.2019

    • Author(s)
      Tan YH, Shudo T, Yoshida T, Sugiyama Y, Si JY, Tsukano C, Takemoto Y, Kakizuka A.
    • Journal Title

      Genes Cells.

      Volume: 24 Issue: 11 Pages: 688-704

    • DOI

      10.1111/gtc.12719

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] KUS121, a valosin-containing protein modulator, attenuates ischemic stroke via preventing ATP depletion.2019

    • Author(s)
      Kinoshita H, Maki T, Yasuda K, Kishida N, Sasaoka N, Takagi Y, Kakizuka A, Takahashi R.
    • Journal Title

      Sci Rep.

      Volume: 9 Issue: 1 Pages: 11519-11519

    • DOI

      10.1038/s41598-019-47993-w

    • NAID

      120006786947

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Emodin, as a mitochondrial uncoupler, induces strong decreases in ATP levels and proliferation of B16F10 cells, owing to their poor glycolytic reserve.2019

    • Author(s)
      Sugiyama, U., Shudo, T., Hosokawa, S., Watanabe, A., Nakano, M., Kakizuka, A.
    • Journal Title

      Genes to Cells

      Volume: 8 Issue: 8 Pages: 569-584

    • DOI

      10.1111/gtc.12712

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 難治性疾患への挑戦2020

    • Author(s)
      垣塚 彰
    • Organizer
      東海医学会講演会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 難治性疾患克服への挑戦2019

    • Author(s)
      垣塚 彰
    • Organizer
      第21回生命科学研究科シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Remarks] 京大開発の薬剤「KUS121」の変形性膝関節症への効果を確認

    • URL

      https://www.kyoto-u.ac.jp/ja/research-news/2020-12-17-1

    • Related Report
      2020 Annual Research Report
  • [Remarks] 京都大学大学院生命科学研究科高次生体統御学ホームページ

    • URL

      http://www.funcbiol.lif.kyoto-u.ac.jp/

    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 腎臓保護用の組成物2020

    • Inventor(s)
      垣塚彰、池田華子、桒原孝成
    • Industrial Property Rights Holder
      国立大学法人京都大学、国立大学法人熊本大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-194628
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 軟骨保護用の医薬組成物2020

    • Inventor(s)
      垣塚彰、西谷江平、池田華子、他4名
    • Industrial Property Rights Holder
      国立大学法人京都大学、京都創薬株式会社
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
    • Overseas

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Published: 2019-04-18   Modified: 2024-01-30  

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