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Drug discovery based on collateral lethality

Research Project

Project/Area Number 17K19586
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Research Field Tumor biology and related fields
Research InstitutionKanazawa University

Principal Investigator

Takahashi Chiaki  金沢大学, がん進展制御研究所, 教授 (50283619)

Research Collaborator Kohno Susumu  
Project Period (FY) 2017-06-30 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywordsがん / 代謝 / SUCLA2 / 合成致死性 / RB / SUCLG2 / 創薬標的 / がん代謝 / ゲノム異常 / パッセンジャー欠失
Outline of Final Research Achievements

Initially, we thought that inhibition of SUCLG2, which is an isozyme of SUCLA2, exerts synthetic lethality, but the effect was limited. Therefore, we created a prostate cancer cell line lacking SUCLA2 and a prostate cancer cell line in which SUCLA2 was reconstituted. Using the CRISPR-CAS9 library, we searched genes those dropped specifically in prostate cancer cell lines lacking SUCLA2, and obtained 8 candidate genes. Furthermore, we screened for compounds that induce cell death specifically in SUCLA2-deficient prostate cancer, and to date, from the screening of natural compound libraries, we found two compounds are specifically cytotoxic for SUCLA2-deleted strains.

Academic Significance and Societal Importance of the Research Achievements

RB遺伝子の近傍に位置するSUCLA2が、RB遺伝子領域の欠失に極めて頻繁に巻き込まれることが判った。SUCLA2は重要な代謝酵素をコードするので、この遺伝子欠損と合成致死性を示す標的分子を探索した。遺伝子欠損が合成致死性を発揮する遺伝子を8種、その作用が合成致死性を発揮する化合物2種を特定した。特定のゲノム異常を持つがんを標的にする副作用の少ない薬剤の開発につながると思われる。

Report

(3 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • Research Products

    (16 results)

All 2018 2017 Other

All Journal Article (10 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 9 results,  Open Access: 7 results,  Acknowledgement Compliant: 1 results) Presentation (2 results) Book (1 results) Remarks (3 results)

  • [Journal Article] Regucalcin confers resistance to amyloid-β toxicity in neuronally differentiated PC12 cells2018

    • Author(s)
      Murata Tomiyasu、Yamaguchi Masayoshi、Kohno Susumu、Takahashi Chiaki、Kakimoto Mitsumi、Sugimura Yukiko、Kamihara Mako、Hikita Kiyomi、Kaneda Norio
    • Journal Title

      FEBS Open Bio

      Volume: 8 Issue: 3 Pages: 349-360

    • DOI

      10.1002/2211-5463.12374

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Involvement of prokineticin 2-expressing neutrophil infiltration in 5-fluorouracil-induced aggravation of breast cancer metastasis to lung.2018

    • Author(s)
      Sasaki S, Baba T, Muranaka H, Tanabe Y, Takahashi C, Matsugo S, Mukaida N.
    • Journal Title

      Mol Cancer Ther

      Volume: 印刷中 Issue: 7 Pages: 1515-1525

    • DOI

      10.1158/1535-7163.mct-17-0845

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sphingosine-1-phosphate receptor-2 facilitates pulmonary fibrosis through potentiating IL-13 pathway in macrophages.2018

    • Author(s)
      Zhao J, Okamoto Y, Asano Y, Ishimaru K, Aki S, Yoshioka K, Takuwa N, Wada T, Inagaki Y, Takahashi C, Nishiuchi T, Takuwa Y.
    • Journal Title

      PLoS One

      Volume: 13(5)

    • NAID

      120006605152

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS2018

    • Author(s)
      Kitajima Shunsuke et al.
    • Journal Title

      Cancer Cell

      Volume: 34 Issue: 3 Pages: 439-452.e6

    • DOI

      10.1016/j.ccell.2018.08.009

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD22018

    • Author(s)
      Nishimura Tatsunori、Nakata Asuka、Chen Xiaoxi、Nishi Kurumi、Meguro-Horike Makiko、Sasaki Soichiro、Kita Kenji、Horike Shin-ichi、Saitoh Kaori、Kato Keiko、Igarashi Kaori、Murayama Takahiko、Kohno Susumu、Takahashi Chiaki、Mukaida Naofumi、Yano Seiji、Soga Tomoyoshi、Tojo Arinobu、Gotoh Noriko
    • Journal Title

      Oncogene

      Volume: 38 Issue: 14 Pages: 2464-2481

    • DOI

      10.1038/s41388-018-0589-1

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The RB?IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity2017

    • Author(s)
      Kitajima S、Yoshida A、Kohno S、Li F、Suzuki S、Nagatani N、Nishimoto Y、Sasaki N、Muranaka H、Wan Y、Thai T C、Okahashi N、Matsuda F、Shimizu H、Nishiuchi T、Suzuki Y、Tominaga K、Gotoh N、Suzuki M、Ewen M E、Barbie D A、Hirose O、Tanaka T、Takahashi C
    • Journal Title

      Oncogene

      Volume: 36 Issue: 36 Pages: 5145-5157

    • DOI

      10.1038/onc.2017.124

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] MicroRNA-140 mediates RB tumor suppressor function to control stem cell-like activity through interleukin-6.2017

    • Author(s)
      Yoshida A, Kitajima S, Li F, Chaoyang C, Yujiro T, Susumu K, Wan Y, Naoyuki H, Hayato M, Nishimoto Y, Nagatani N, Nishiuchi T, Thai T C, Suzuki S, Nakao S, Tanaka T, Hirose O, Barbie D A and Takahashi C.
    • Journal Title

      Oncotarget

      Volume: 印刷中 Issue: 8 Pages: 13872-85

    • DOI

      10.18632/oncotarget.14681

    • NAID

      120006226780

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] A distinct function of the retinoblastoma protein in the control of lipid composition identified by lipidomic profiling2017

    • Author(s)
      Muranaka H、Hayashi A、Minami K、Kitajima S、Kohno S、Nishimoto Y、Nagatani N、Suzuki M、Kulathunga L A N、Sasaki N、Okada N、Matsuzaka T、Shimano H、Tada H、Takahashi C
    • Journal Title

      Oncogenesis

      Volume: 6 Issue: 6 Pages: e350-e350

    • DOI

      10.1038/oncsis.2017.51

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Glucoraphanin ameliorates obesity and insulin resistance through adipose tissue browning and reduction of metabolic endotoxemia in mice.2017

    • Author(s)
      Nagata N, Xu L, Kohno S, Ushida Y, Aoki Y, Umeda R, Fuke N, Zhuge F, Ni Y, Nagashimada M, Takahashi C, Suganuma H, Kaneko S and Ota T.
    • Journal Title

      Diabetes

      Volume: 印刷中 Issue: 5 Pages: 1222-1236

    • DOI

      10.2337/db16-0662

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Intersection of retinoblastoma tumor suppressor function, stem cells, metabolism, and inflammation2017

    • Author(s)
      Kitajima Shunsuke、Takahashi Chiaki
    • Journal Title

      Cancer Science

      Volume: 108 Issue: 9 Pages: 1726-1731

    • DOI

      10.1111/cas.13312

    • NAID

      120006370944

    • Related Report
      2017 Research-status Report
  • [Presentation] 前立腺がんにおけるRBホモ欠損に伴う脆弱性の獲得.2018

    • Author(s)
      河野晋, Paing Linn, 髙橋智聡.
    • Organizer
      第5回がんと代謝研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 前立腺がんにおけるRBホモ欠損に伴う脆弱性の獲得2017

    • Author(s)
      河野晋, Paing Linn, 髙橋智聡
    • Organizer
      第5回がんと代謝研究会
    • Related Report
      2017 Research-status Report
  • [Book] 実験医学増刊号「RBとがんの代謝」2017

    • Author(s)
      河野晋、村中勇人、北嶋俊輔、佐々木信成、鈴木美砂、髙橋智聡
    • Total Pages
      5
    • Publisher
      羊土社
    • Related Report
      2017 Research-status Report
  • [Remarks] 髙橋智聡研究室HP

    • URL

      http://omb.w3.kanazawa-u.ac.jp/index.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] 金沢大学がん進展制御研究所ホームページ

    • URL

      http://ganken.cri.kanazawa-u.ac.jp

    • Related Report
      2017 Research-status Report
  • [Remarks] 髙橋智聡研究室ホームページ

    • URL

      http://omb.w3.kanazawa-u.ac.jp/index.html

    • Related Report
      2017 Research-status Report

URL: 

Published: 2017-07-21   Modified: 2020-03-30  

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