並列タイトル等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
タイトル（掲載誌）The Journal of biological chemistry
一般注記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
DOIinfo:doi/10.1074/jbc.RA120.013726
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