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Cell Fate Decisions

DNA Replication Stress Induced by Trifluridine Determines Tumor Cell Fate According to p53 Status

Yuki Kataoka, Makoto Iimori, Ryo Fujisawa, Tomomi Morikawa-Ichinose, Shinichiro Niimi, Takeshi Wakasa, Hiroshi Saeki, Eiji Oki, Daisuke Miura, Toshiki Tsurimoto, Yoshihiko Maehara and Hiroyuki Kitao
Yuki Kataoka
1Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
2Taiho Pharmaceutical Co. Ltd., Tokyo, Japan.
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  • ORCID record for Yuki Kataoka
Makoto Iimori
1Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
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Ryo Fujisawa
3Division of Biological Sciences, Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.
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Tomomi Morikawa-Ichinose
4Metabolic Profiling Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
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Shinichiro Niimi
5Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
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Takeshi Wakasa
1Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
2Taiho Pharmaceutical Co. Ltd., Tokyo, Japan.
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Hiroshi Saeki
6Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
7Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan.
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Eiji Oki
6Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Daisuke Miura
4Metabolic Profiling Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
8Advanced Biomeasurements Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan.
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Toshiki Tsurimoto
3Division of Biological Sciences, Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.
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Yoshihiko Maehara
5Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
6Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
9Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, Japan.
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Hiroyuki Kitao
1Department of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
5Innovative Anticancer Strategy for Therapeutics and Diagnosis Group, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
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  • For correspondence: hkitao@phar.kyushu-u.ac.jp
DOI: 10.1158/1541-7786.MCR-19-1051 Published September 2020
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Abstract

DNA replication stress (DRS) is a predominant cause of genome instability, a driver of tumorigenesis and malignant progression. Nucleoside analogue-type chemotherapeutic drugs introduce DNA damage and exacerbate DRS in tumor cells. However, the mechanisms underlying the antitumor effect of these drugs are not fully understood. Here, we show that the fluorinated thymidine analogue trifluridine (FTD), an active component of the chemotherapeutic drug trifluridine/tipiracil, delayed DNA synthesis by human replicative DNA polymerases by acting both as an inefficient deoxyribonucleotide triphosphate source (FTD triphosphate) and as an obstacle base (trifluorothymine) in the template DNA strand, which caused DRS. In cells, FTD decreased the thymidine triphosphate level in the dNTP pool and increased the FTD triphosphate level, resulting in the activation of DRS-induced cellular responses during S-phase. In addition, replication protein A–coated single-stranded DNA associated with FancD2 and accumulated after tumor cells completed S-phase. Finally, FTD activated the p53–p21 pathway and suppressed tumor cell growth by inducing cellular senescence via mitosis skipping. In contrast, tumor cells that lost wild-type p53 underwent apoptotic cell death via aberrant late mitosis with severely impaired separation of sister chromatids. These results demonstrate that DRS induced by a nucleoside analogue–type chemotherapeutic drug suppresses tumor growth irrespective of p53 status by directing tumor cell fate toward cellular senescence or apoptotic cell death according to p53 status.

Implications: Chemotherapeutic drugs that increase DRS during S-phase but allow tumor cells to complete S-phase may have significant antitumor activity even when functional p53 is lost.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1354–66

  • Received October 25, 2019.
  • Revision received April 15, 2020.
  • Accepted May 21, 2020.
  • Published first May 28, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (9)
September 2020
Volume 18, Issue 9
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DNA Replication Stress Induced by Trifluridine Determines Tumor Cell Fate According to p53 Status
Yuki Kataoka, Makoto Iimori, Ryo Fujisawa, Tomomi Morikawa-Ichinose, Shinichiro Niimi, Takeshi Wakasa, Hiroshi Saeki, Eiji Oki, Daisuke Miura, Toshiki Tsurimoto, Yoshihiko Maehara and Hiroyuki Kitao
Mol Cancer Res September 1 2020 (18) (9) 1354-1366; DOI: 10.1158/1541-7786.MCR-19-1051

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DNA Replication Stress Induced by Trifluridine Determines Tumor Cell Fate According to p53 Status
Yuki Kataoka, Makoto Iimori, Ryo Fujisawa, Tomomi Morikawa-Ichinose, Shinichiro Niimi, Takeshi Wakasa, Hiroshi Saeki, Eiji Oki, Daisuke Miura, Toshiki Tsurimoto, Yoshihiko Maehara and Hiroyuki Kitao
Mol Cancer Res September 1 2020 (18) (9) 1354-1366; DOI: 10.1158/1541-7786.MCR-19-1051
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Molecular Cancer Research
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