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

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  • Additional Information
    • Source:
      Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101150042 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3125 (Electronic) Linking ISSN: 15417786 NLM ISO Abbreviation: Mol Cancer Res Subsets: MEDLINE
    • Publication Information:
      Original Publication: Philadelphia, PA : American Association for Cancer Research, c2002-
    • Subject Terms:
      Antiviral Agents/*therapeutic use ; DNA Replication/*drug effects ; Trifluridine/*therapeutic use ; Tumor Suppressor Protein p53/*genetics; Animals ; Antiviral Agents/pharmacology ; Humans ; Male ; Mice ; Mice, Nude ; Trifluridine/pharmacology
    • 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.
      (©2020 American Association for Cancer Research.)
    • Accession Number:
      0 (Antiviral Agents)
      0 (Tumor Suppressor Protein p53)
      RMW9V5RW38 (Trifluridine)
    • Publication Date:
      Date Created: 20200530 Date Completed: 20210810 Latest Revision: 20210810
    • Publication Date:
      20240829
    • Accession Number:
      10.1158/1541-7786.MCR-19-1051
    • Accession Number:
      32467171