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Molecular mechanism of therapy-induced senescence caused by replicative stress

Research Project

Project/Area Number 17H03598
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor therapeutics
Research InstitutionKyushu University

Principal Investigator

Kitao Hiroyuki  九州大学, 薬学研究院, 教授 (30368617)

Co-Investigator(Kenkyū-buntansha) 飯森 真人  九州大学, 薬学研究院, 准教授 (20546460)
釣本 敏樹  九州大学, 理学研究院, 教授 (30163885)
沖 英次  九州大学, 大学病院, 講師 (70380392)
佐伯 浩司  群馬大学, 大学院医学系研究科, 教授 (80325448)
三浦 大典  九州大学, 農学研究院, 特任准教授 (40532627)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
Fiscal Year 2019: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2017: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Keywords抗がん剤 / DNA複製ストレス / 治療誘導性細胞老化 / がん化学療法 / 複製ストレス / 細胞老化 / M期スキップ
Outline of Final Research Achievements

Therapy-induced senescence is now recognized as an important mechanism that elucidates irreversible cell cycle arrest induced by chemotherapeutic drugs. In this research project, we found that trifluridine, a cytotoxic component of chemotherapeutic drug FTD/TPI, efficiently induced cellular senescence in the cell culture condition and DNA replication stress induced by trifluridine was the trigger. In tumor cells, trifluridine, as a fluorinated thymidine analog, was incorporated into genomic DNA during DNA replication process. At that process, trifluridine decreased the efficiency of DNA replication. As a result, single-strand DNA was exposed in the nucleus, p53 was activated, and cellular senescence was induced. In the tumor cells with p53 deficiency, apoptosis was induced as a result of abnormal sister chromatid separation.

Academic Significance and Societal Importance of the Research Achievements

FTD/TPIは進行大腸癌・胃癌に対する抗がん剤として世界で広く治療に用いられている。本研究成果は、FTD/TPIの抗腫瘍効果を担うFTDの作用メカニズムの理解に必須の知見である。さらに、悪性度を増したヒト腫瘍で多く見られ、抗がん剤耐性に繋がるとされるp53欠損を持つがん細胞であってもFTDが抗腫瘍効果を発揮するという結果は、このメカニズムに基づく抗がん剤治療がp53変異に関わらず有効であることを示唆しており、今後の抗がん剤開発を考える上でも意義は大きい。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (21 results)

All 2020 2019 2018 2017 Other

All Journal Article (12 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 11 results,  Open Access: 6 results) Presentation (8 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results) Remarks (1 results)

  • [Journal Article] Detection of trifluridine in tumors of patients with metastatic colorectal cancer treated with trifluridine/tipiracil.2020

    • Author(s)
      Fujimoto Yoshiaki, Nakanishi Ryota, Nukatsuka Mamoru, Matsuoka Kazuaki, Ando Koji, Wakasa Takeshi, Kitao Hiroyuki, Oki Eiji, Maehara Yoshihiko, Mori Masaki
    • Journal Title

      Cancer Chemotherapy and Pharmacology

      Volume: - Issue: 6 Pages: 1029-1038

    • DOI

      10.1007/s00280-020-04072-6

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] DNA replication stress induced by trifluridine determines tumor cell fate according to p53 status2020

    • Author(s)
      Kataoka Yuki、Iimori Makoto、Fujisawa Ryo、Morikawa-Ichinose Tomomi、Niimi Shinichiro、Wakasa Takeshi、Saeki Hiroshi、Oki Eiji、Miura Daisuke、Tsurimoto Toshiki、Maehara Yoshihiko、Kitao Hiroyuki
    • Journal Title

      Molecular Cancer Research

      Volume: - Issue: 9 Pages: 1354-1366

    • DOI

      10.1158/1541-7786.mcr-19-1051

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cytotoxicity of trifluridine correlates with the thymidine kinase 1 expression level2019

    • Author(s)
      Kataoka Yuki、Iimori Makoto、Niimi Shinichiro、Tsukihara Hiroshi、Wakasa Takeshi、Saeki Hiroshi、Oki Eiji、Maehara Yoshihiko、Kitao Hiroyuki
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 7964-7964

    • DOI

      10.1038/s41598-019-44399-6

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] MDC1 methylation mediated by lysine methyltransferases EHMT1 and EHMT2 regulates active ATM accumulation flanking DNA damage sites2018

    • Author(s)
      Watanabe Sugiko、Iimori Makoto、Chan David Virya、Hara Eiji、Kitao Hiroyuki、Maehara Yoshihiko
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 10888-10888

    • DOI

      10.1038/s41598-018-29239-3

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Thymidine Kinase 1 Loss Confers Trifluridine Resistance without Affecting 5-Fluorouracil Metabolism and Cytotoxicity2018

    • Author(s)
      Edahiro Keitaro、Iimori Makoto、Kobunai Takashi、Morikawa-Ichinose Tomomi、Miura Daisuke、Kataoka Yuki、Niimi Shinichiro、Wakasa Takeshi、Saeki Hiroshi、Oki Eiji、Kitao Hiroyuki、Maehara Yoshihiko
    • Journal Title

      Molecular Cancer Research

      Volume: 16 Issue: 10 Pages: 1483-1490

    • DOI

      10.1158/1541-7786.mcr-17-0686

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair2018

    • Author(s)
      Bharti Sanjay Kumar、Sommers Joshua A、Awate Sanket、Bellani Marina A、Khan Irfan、Bradley Lynda、King Graeme A、Seol Yeonee、Vidhyasagar Venkatasubramanian、Wu Yuliang、Abe Takuye、Kobayashi Koji、Shin-ya Kazuo、Kitao Hiroyuki、Wold Marc S、Branzei Dana、Neuman Keir C、Brosh Robert M
    • Journal Title

      Nucleic Acids Research

      Volume: 46 Issue: 12 Pages: 6238-6256

    • DOI

      10.1093/nar/gky403

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Epithelial Paradox: Clinical Significance of Coexpression of E-cadherin and Vimentin With?Regard to Invasion and Metastasis of Breast?Cancer2018

    • Author(s)
      Yamashita Nami、Tokunaga Eriko、Iimori Makoto、Inoue Yuka、Tanaka Kimihiro、Kitao Hiroyuki、Saeki Hiroshi、Oki Eiji、Maehara Yoshihiko
    • Journal Title

      Clinical Breast Cancer

      Volume: 印刷中 Issue: 5 Pages: e1003-e1009

    • DOI

      10.1016/j.clbc.2018.02.002

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] DNA replication stress and cancer chemotherapy2018

    • Author(s)
      Kitao Hiroyuki、Iimori Makoto、Kataoka Yuki、Wakasa Takeshi、Tokunaga Eriko、Saeki Hiroshi、Oki Eiji、Maehara Yoshihiko
    • Journal Title

      Cancer Science

      Volume: 109 Issue: 2 Pages: 264-271

    • DOI

      10.1111/cas.13455

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Activation of the FA pathway mediated by phosphorylation and ubiquitination2017

    • Author(s)
      Ishiai M., Sato K, Tomida J, Kitao H., Kurumizaka H., Takata M.
    • Journal Title

      Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis

      Volume: 803-805 Pages: 89-95

    • DOI

      10.1016/j.mrfmmm.2017.05.003

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mitotic slippage and the subsequent cell fates after inhibition of Aurora B during tubulin-binding agent?induced mitotic arrest2017

    • Author(s)
      Tsuda Yasuo、Iimori Makoto、Nakashima Yuichiro、Nakanishi Ryota、Ando Koji、Ohgaki Kippei、Kitao Hiroyuki、Saeki Hiroshi、Oki Eiji、Maehara Yoshihiko
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 16762-16762

    • DOI

      10.1038/s41598-017-17002-z

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Monitoring trifluridine incorporation in the peripheral blood mononuclear cells of colorectal cancer patients under trifluridine/tipiracil medication2017

    • Author(s)
      Nakanishi Ryota、Kitao Hiroyuki、Kiniwa Mamoru、Morodomi Yosuke、Iimori Makoto、Kurashige Junji、Sugiyama Masahiko、Nakashima Yuichiro、Saeki Hiroshi、Oki Eiji、Maehara Yoshihiko
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 16969-16969

    • DOI

      10.1038/s41598-017-17282-5

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical Significance of the Wild Type p53-Induced Phosphatase 1 Expression in Invasive Breast Cancer2017

    • Author(s)
      Inoue Yuka、Yamashita Nami、Kitao Hiroyuki、Tanaka Kimihiro、Saeki Hiroshi、Oki Eiji、Oda Yoshinao、Tokunaga Eriko、Maehara Yoshihiko
    • Journal Title

      Clinical Breast Cancer

      Volume: 印刷中 Issue: 4 Pages: e643-e650

    • DOI

      10.1016/j.clbc.2017.11.008

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Cell fate decision according to p53 status in response to nucleoside analog-induced DNA replication stress2018

    • Author(s)
      Hiroyuki Kitao
    • Organizer
      Gordon Research Conference-Mutagenesis
    • Related Report
      2018 Annual Research Report
  • [Presentation] The mechanism of tumor cell fate decision by an antitumor nucleoside analogue, trifluridine2018

    • Author(s)
      Hiroyuki KItao
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Cell fate decision according to p53 status in response to nucleoside analog-induced DNA replication stress2018

    • Author(s)
      Hiroyuki Kitao
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] トリフルリジン誘導性DNA複製ストレスががん細胞の運命に及ぼす影響2017

    • Author(s)
      北尾洋之、片岡裕貴、飯森真人、藤澤遼、 釣本敏樹、一瀬智美、三浦大典、松岡和明、沖英次、佐伯浩司、前原喜彦
    • Organizer
      第21回日本がん分子標的治療学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Replicative stress in the induction of p53-dictated cytotoxicity by an antitumor nucleoside analogue, trifluridine.2017

    • Author(s)
      北尾洋之、片岡裕貴、飯森真人、藤澤遼、 釣本敏樹、一瀬智美、三浦大典、松岡和明、沖英次、佐伯浩司、前原喜彦
    • Organizer
      29th Fanconi Anemia Research Fund Annual Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] トリフルリジン誘導性DNA複製ストレスががん細胞の運命に及ぼす影響2017

    • Author(s)
      北尾洋之、片岡裕貴、飯森真人、藤澤遼、 釣本敏樹、一瀬智美、三浦大典、松岡和明、沖英次、佐伯浩司、前原喜彦
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Annual Research Report
  • [Presentation] トリフルリジン・チピラシルによる治療効果の基礎・臨床での評価2017

    • Author(s)
      北尾 洋之、飯森真人、中西良太、佐伯浩司、沖英次、前原喜彦
    • Organizer
      第35回日本ヒト細胞学会学術集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] ヌクレオチドアナログ誘導性DNA複製ストレスとp53を介した細胞運命2017

    • Author(s)
      北尾洋之、飯森真人、片岡裕貴、藤澤遼、釣本敏樹、一瀬智美、三浦大典、若狹武司、松岡和明、佐伯浩司、沖英次、前原喜彦
    • Organizer
      第40回日本分子生物学会総会
    • Related Report
      2017 Annual Research Report
  • [Remarks] 九州大学 研究者情報

    • URL

      http://hyoka.ofc.kyushu-u.ac.jp/search/details/K003932/index.html

    • Related Report
      2018 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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