期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 295, 期 37, 页码 12946-12961出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.013726
关键词
ATR serine; threonine kinase; 5-fluorouracil; cell-cycle checkpoint; DNA double-strand breaks; homologous recombination; BRCA2; cancer; apoptosis; antineoplastic agent; chemotherapy; DNA repair; DNA damage response; cell cycle; anticancer drug
资金
- Japan Society for the Promotion of Science (JSPS) KAKENHI [JP18K17234, JP20H03199, JP19K08150, JP19K23976, JP19K21306, JP20K16583, JP18K07764, JP19K10272]
- AMED Brain/MINDS Beyond Grant [JP20dm0307032]
- Takeda Science Foundation
- Kanzawa Medical Research Foundation
- Uehara Memorial Foundation
- Nakatomi Foundation
- Konica Minolta Science and Technology Foundation
- Naito Foundation
- MSD Life Science Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- SENSHIN Medical Research Foundation
- Terumo Foundation for Life Sciences and Arts
- Nara Kidney Disease Research Foundation
- Novartis Research
- Sumitomo Dainippon Pharma Research
- Tokyo Biochemical Research Foundation
- KTX Corp., Aichi, Japan
- Koseikan, Nara, Japan
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 lackingBRCA2were 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.
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