Drug discovery based on collateral lethality

• Project/Area Number: 17K19586
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: Kanazawa 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: ¥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。

Research Products

• [Journal Article] Regucalcin confers resistance to amyloid-β toxicity in neuronally differentiated PC12 cells (2018)
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS (2018)
  • 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
  • Peer Reviewed
• [Journal Article] Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2 (2018)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] The RB?IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity (2017)
  • 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
  • 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
  • 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 profiling (2017)
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intersection of retinoblastoma tumor suppressor function, stem cells, metabolism, and inflammation (2017)
  • Author(s): Kitajima Shunsuke、Takahashi Chiaki
  • Journal Title: Cancer Science Volume: 108 Issue: 9 Pages: 1726-1731
  • DOI: 10.1111/cas.13312
  • NAID: 120006370944
• [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
• [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
• [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
• [Remarks] 髙橋智聡研究室HP
  • URL: http://omb.w3.kanazawa-u.ac.jp/index.html
• [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
• [Remarks] 髙橋智聡研究室ホームページ
  • URL: http://omb.w3.kanazawa-u.ac.jp/index.html