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Elucidation of the ASK family-regulated mechanism of cancer metastasis and search for inhibitors

Research Project

Project/Area Number 18K19469
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 50:Oncology and related fields
Research InstitutionThe University of Tokyo

Principal Investigator

Ichijo Hidenori  東京大学, 大学院薬学系研究科(薬学部), 教授 (00242206)

Project Period (FY) 2018-06-29 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
KeywordsASKファミリー / がん転移 / 阻害剤スクリーニング
Outline of Final Research Achievements

For project (A), we analyzed the phenotypes of knockout (KO) mice of Apoptosis signal-regulating kinase (ASK) family in the experimental metastasis model and revealed that attenuation of lung metastasis is specific to ASK1 KO mice, but not ASK2 KO or ASK3 KO mice. For project (B), we examined the side effects of inhibiting ASK family in endothelial cells (ECs) and revealed that ASK1 inhibition in ECs leads to contradictory phenotypes between in vivo and in vitro. Thus we concluded that ASK1 inhibition in ECs needs cautious investigation. For project (C), we decided to use anti-tumor natural killer (NK) cell-specific cre-expressing mice for in vivo screening of ASK family inhibitors.

Academic Significance and Societal Importance of the Research Achievements

申請者らはASKファミリーの長年の解析を通して得た知見を元に、ASK1ががん転移を多面的に制御することを明らかにしてきた。本研究はASKファミリーの阻害標的としての有用性の網羅的かつ統合的な解析と、in vitroとin vivo双方の阻害剤スクリーニングを提案した。がん転移治療法確立や阻害剤の開発が進まない一因として、がん細胞が最終的に転移巣を形成する確率が低く、in vivoでの阻害剤の評価が困難であることが挙げられる。本研究はASKファミリー分子に焦点を当て、新規がん転移阻害剤の探索を目的としており、がん転移の治療法確立に向けた基礎的研究として学術的及び社会的に大きな意義を持つ。

Report

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

    (24 results)

All 2020 2019 2018 2017

All Journal Article (15 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 15 results,  Open Access: 12 results) Presentation (9 results)

  • [Journal Article] Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu/Zn superoxide dismutase.2020

    • Author(s)
      Homma, K., Takahashi, H., Tsuburaya, N., Naguro, I., Fujisawa, T. and Ichijo, H.
    • Journal Title

      J. Biol. Chem.

      Volume: 295 Issue: 10 Pages: 3148-3158

    • DOI

      10.1074/jbc.ra119.010239

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue.2020

    • Author(s)
      Kato H, Okabe K, Miyake M, Hattori K, Fukaya T, Tanimoto K, Beini S, Mizuguchi M, Torii S, Arakawa S, Ono M, Saito Y, Sugiyama T, Funatsu T, Sato K, Shimizu S, Oyadomari S, Ichijo H, Kadowaki H, Nishitoh H.
    • Journal Title

      Life science alliance

      Volume: 3 Issue: 3 Pages: 201900576-201900576

    • DOI

      10.26508/lsa.201900576

    • NAID

      120006980545

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ASK1 promotes uterine inflammation leading to pathological preterm birth2020

    • Author(s)
      Yoshikawa Midori、Iriyama Takayuki、Suzuki Kensuke、Sayama Seisuke、Tsuruga Tetsushi、Kumasawa Keiichi、Nagamatsu Takeshi、Homma Kengo、Naguro Isao、Osuga Yutaka、Ichijo Hidenori、Fujii Tomoyuki
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 1887-1887

    • DOI

      10.1038/s41598-020-58653-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1.2020

    • Author(s)
      Sugawara, S., Kanamaru, Y., Sekine, S., Maekawa, L., Takahashi, A., Yamamoto, T., Watanabe, K., Fujisawa, T., Hattori, K. and Ichijo, H.
    • Journal Title

      J. Biol. Chem.

      Volume: 295 Issue: 17 Pages: 5588-5601

    • DOI

      10.1074/jbc.ra119.011508

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases.2019

    • Author(s)
      Nakamura, T., Naguro, I. and Ichijo, H.
    • Journal Title

      Biochim. Biophys. Acta. Gen. Subj.

      Volume: pii Issue: 9 Pages: 1398-1409

    • DOI

      10.1016/j.bbagen.2019.06.010

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cell volume regulation in cancer cell migration driven by osmotic water flow2019

    • Author(s)
      Morishita Kazuhiro、Watanabe Kengo、Ichijo Hidenori
    • Journal Title

      Cancer Science

      Volume: 110 Issue: 8 Pages: 2337-2347

    • DOI

      10.1111/cas.14079

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] β-TrCP-dependent degradation of ASK1 suppresses the induction of the apoptotic response by oxidative stress2018

    • Author(s)
      Cheng Ran、Takeda Kohsuke、Naguro Isao、Hatta Tomohisa、Iemura Shun-ichiro、Natsume Tohru、Ichijo Hidenori、Hattori Kazuki
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - General Subjects

      Volume: 1862 Issue: 10 Pages: 2271-2280

    • DOI

      10.1016/j.bbagen.2018.07.015

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model2018

    • Author(s)
      Tsuburaya, N., Homma, K., Higuchi, T., Balia, A., Yamakoshi, H., Shibata, N., Nakamura, S., Nakagawa, H., Ikeda, S., Umezawa, N., Kato, N., Yokoshima, S., Shibuya, M., Shimonishi, M., Kojima, H., Okabe, T., Nagano, T., Naguro, I., Imamura, K., Inoue, H., Fujisawa, T., and Ichijo, H.
    • Journal Title

      Nature Communications

      Volume: 9 Issue: 1 Pages: 2668-2668

    • DOI

      10.1038/s41467-018-05127-2

    • NAID

      120006546002

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cryo-EM structure of the volume-regulated anion channel LRRC82018

    • Author(s)
      Kasuya Go、Nakane Takanori、Yokoyama Takeshi、Jia Yanyan、Inoue Masato、Watanabe Kengo、Nakamura Ryoki、Nishizawa Tomohiro、Kusakizako Tsukasa、Tsutsumi Akihisa、Yanagisawa Haruaki、Dohmae Naoshi、Hattori Motoyuki、Ichijo Hidenori、Yan Zhiqiang、Kikkawa Masahide、Shirouzu Mikako、Ishitani Ryuichiro、Nureki Osamu
    • Journal Title

      Nat. Struct. Mol. Biol.

      Volume: 25 Pages: 797-804

    • DOI

      10.1101/331207

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] ASK family kinases mediate cellular stress and redox signaling to circadian clock2018

    • Author(s)
      Imamura Kiyomichi、Yoshitane Hikari、Hattori Kazuki、Yamaguchi Mitsuo、Yoshida Kento、Okubo Takenori、Naguro Isao、Ichijo Hidenori、Fukada Yoshitaka
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 115 Issue: 14 Pages: 3646-3651

    • DOI

      10.1073/pnas.1719298115

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A PP6-ASK3 Module Coordinates the Bidirectional Cell Volume Regulation under Osmotic Stress2018

    • Author(s)
      Watanabe Kengo、Umeda Tsuyoshi、Niwa Kuniyoshi、Naguro Isao、Ichijo Hidenori
    • Journal Title

      Cell Reports

      Volume: 22 Issue: 11 Pages: 2809-2817

    • DOI

      10.1016/j.celrep.2018.02.045

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.2018

    • Author(s)
      Galluzzi, L. et al.
    • Journal Title

      Cell Death Differ.

      Volume: 25 Issue: 3 Pages: 486-541

    • DOI

      10.1038/s41418-017-0012-4

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] mASKing cancer cells in a tumor microenvironment2018

    • Author(s)
      Kamiyama Miki、Naguro, Isao、Ichijo Hidenori
    • Journal Title

      Cell Cycle

      Volume: 17 Issue: 2 Pages: 139-140

    • DOI

      10.1080/15384101.2017.1407402

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Apoptosis signal-regulating kinase 1 in regulated necrosis2018

    • Author(s)
      Hattori Kazuki、Ichijo Hidenori
    • Journal Title

      Cell Cycle

      Volume: 17 Issue: 1 Pages: 5-6

    • DOI

      10.1080/15384101.2017.1397330

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer’s Disease and Brain Aging2017

    • Author(s)
      Hasegawa Yu、Toyama Kensuke、Uekawa Ken、Ichijo Hidenori、Kim-Mitsuyama Shokei
    • Journal Title

      Journal of Alzheimer's Disease

      Volume: 61 Issue: 1 Pages: 259-263

    • DOI

      10.3233/jad-170645

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] ASK1はアシアロGM1陽性細胞を介してがん転移を負に制御する2019

    • Author(s)
      藤本磨琴,神山美樹,名黒功,一條秀憲
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] ASK1はNK細胞依存的にがん転移を制御する2019

    • Author(s)
      藤本磨琴,神山美樹,名黒功,一條秀憲
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 血小板におけるASK1がADP受容体P2Y12のリン酸化を介して肺へのがん転移を制御する2018

    • Author(s)
      神山美樹, 大亀美桜, 名黒功, 一條秀憲
    • Organizer
      第22回日本がん分子標的治療学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 血管内皮細胞におけるASK1が肺へのがん転移を制御する2018

    • Author(s)
      古川夏輝, 神山美樹, 名黒功, 一條秀憲
    • Organizer
      第22回日本がん分子標的治療学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 抗腫瘍性免疫におけるASK1の機能解析,2018

    • Author(s)
      藤本磨琴, 神山美樹, 名黒功, 一條秀憲,
    • Organizer
      第22回日本がん分子標的治療学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Functional analysis of ASK family in hemostasis and tumor metastasis2018

    • Author(s)
      Kamiyama, M., Naguro, I., Ichijo, H.
    • Organizer
      第40回日本血栓止血学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] マウスを用いたがん転移におけるASKファミリーの機能解析2018

    • Author(s)
      神山美樹
    • Organizer
      第27回日本がん転移学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 血管内皮細胞におけるASK1が肺へのがん転移を制御する2018

    • Author(s)
      古川夏輝, 神山美樹, 名黒功, 一條秀憲
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] 抗腫瘍性免疫におけるASK1の機能解析2018

    • Author(s)
      藤本磨琴, 神山美樹, 名黒功, 一條秀憲
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report

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Published: 2018-07-25   Modified: 2021-02-19  

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