Inhibition of the ATR kinase enhances 5-FU sensitivity independently of nonhomologous end-joining and homologous recombination repair pathways.

• Material Type: 博士論文
• Title: Inhibition of the ATR kinase enhances 5-FU sensitivity independently of nonhomologous end-joining and homologous recombination repair pathways.
• Author/Editor: Ito, Soichiro S; Nakagawa, Yosuke; Matsubayashi, Masaya; Sakaguchi, Yoshihiko M; Kobashigawa, Shinko; Matsui, Takeshi K; Nanaura, Hitoki; Nakanishi, Mari; Kitayoshi, Fumika; Kikuchi, Sotaro; Kajihara, Atsuhisa; Tamaki, Shigehiro; Sugie, Kazuma; Kashino, Genro; Takahashi, Akihisa; Hasegawa, Masatoshi; Mori, Eiichiro; Kirita, Tadaaki
• Author Heading: Ito, Soichiro S; Nakagawa, Yosuke; Matsubayashi, Masaya; Sakaguchi, Yoshihiko M; Kobashigawa, Shinko; Matsui, Takeshi K; Nanaura, Hitoki; Nakanishi, Mari; Kitayoshi, Fumika; Kikuchi, Sotaro; Kajihara, Atsuhisa; Tamaki, Shigehiro; Sugie, Kazuma; Kashino, Genro; Takahashi, Akihisa; Hasegawa, Masatoshi; Mori, Eiichiro; Kirita, Tadaaki
• Publication, Distribution, etc.: Elsevier
• Publication Date: 2020-09-11
• Publication Date (W3CDTF): 2020-09-11
• Alternative Title: ATR阻害は非相同末端結合および相同組換え修復と非依存的に5-FUを増感する
• Periodical title: The Journal of biological chemistry
• No. or year of volume/issue: 295 37
• Volume: 295
• Issue: 37
• Pages: 12946-12961
• ISSN (Periodical Title): ISSN : 0021-9258
• Degree grantor/type: 奈良県立医科大学
• Date Granted: 2021-03-15
• Dissertation Number: 甲第791号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: ATR serine/threonine kinase; 5-fluorouracil; cell-cycle checkpoint; DNA double-strand breaks; homologous recombination; BRCA2; cancer; apoptosisantineoplastic agent; chemotherapy; DNA repair; DNA damage response; cell cycle; anticancer drug
• Target Audience: 一般
• Note (General): type:Thesis; The anticancer agent 5-fluorouracil (5-FU) is cytotoxic and often used to treat various cancers. 5-FU is thought to inhibit the enzyme thymidylate synthase, which plays a role in nucleotide synthesis and has been found to induce single- and double-strand DNA breaks. ATR Ser/Thr kinase (ATR) is a principal kinase in the DNA damage response and is activated in response to UV- and chemotherapeutic drug-induced DNA replication stress, but its role in cellular responses to 5-FU is unclear. In this study, we examined the effect of ATR inhibition on 5-FU sensitivity of mammalian cells. Using immunoblotting, we found that 5-FU treatment dose-dependently induced the phosphorylation of ATR at the autophosphorylation site Thr-1989 and thereby activated its kinase. Administration of 5-FU with a specific ATR inhibitor remarkably decreased cell survival, compared with 5-FU treatment combined with other major DNA repair kinase inhibitors. Of note, the ATR inhibition enhanced induction of DNA double-strand breaks and apoptosis in 5-FU-treated cells. Using gene expression analysis, we found that 5-FU induced the activation of the intra-S cell-cycle checkpoint. Cells lacking BRCA2 were sensitive to 5-FU in the presence of ATR inhibitor. Moreover, ATR inhibition enhanced the efficacy of the 5-FU treatment, independently of the nonhomologous end-joining and homologous recombination repair pathways. These findings suggest that ATR could be a potential therapeutic target in 5-FU-based chemotherapy.; 博士（医学）・甲第791号・令和3年3月15日; © 2020 Ito et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.; This is an Open Access article under the CC BY license(https://creativecommons.org/licenses/by/4.0/).; identifier:The Journal of biological chemistry Vol.295 No.37 p.12946-12961 (2020 Sep); identifier:00219258; identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/3915; identifier:The Journal of biological chemistry, 295(37): 12946-12961
• Source: fulltext; http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/3915/1/01%e7%94%b2791%e6%9c%ac%e6%96%87%e3%81%ae%e8%a6%81%e6%97%a8.pdf; http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/3915/2/02%e7%94%b2791%e5%af%a9%e6%9f%bb%e8%a6%81%e6%97%a8.pdf; http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/3915/3/03%e7%94%b2791%e6%9c%ac%e6%96%87.pdf; http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/3915/4/04%e7%94%b2791Suppl..pdf
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.1074/jbc.RA120.013726
• Periodical Title (NCID): AA00251083; https://ci.nii.ac.jp/ncid/AA00251083
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 奈良県立医科大学 : 奈良県立医科大学機関リポジトリ GINMU