DNA replication stress induced by trifluridine determines tumor cell fate according to p53 status
DNA replication stress is a predominant cause of genome instability, a driver of tumorigenesis and malignant progression. Nucleoside analog-type chemotherapeutic drugs introduce DNA damage and exacerbate DNA replication stress in tumor cells. However, the mechanisms underlying tumor cytotoxicity triggered by the drugs are not fully understood. Here, we show that the fluorinated thymidine analog trifluridine (FTD), an active component of the chemotherapeutic drug trifluridine/tipiracil, delayed DNA synthesis by human replicative DNA polymerases. FTD acted as an inefficient deoxyribonucleotide triphosphate source (FTD triphosphate) and as an obstacle base (trifluorothymine) in the template DNA strand. At the cellular level, FTD decreased thymidine triphosphate in the dNTP pool and induced FTD triphosphate accumulation, resulting in replication fork stalling caused by FTD incorporation into DNA. DNA lesions involving single-stranded DNA were generated as a result of replication fork stalling, and the p53-p21 pathway was activated. Although FTD suppressed tumor cell growth irrespective of p53 status, tumor cell fate diverged at the G2/M phase transition according to p53 status; tumor cells with wild-type p53 underwent cellular senescence via mitosis skip, whereas tumor cells that lost wild-type p53 underwent apoptotic cell death via aberrant late mitosis with severely impaired separation of sister chromatids. These results suggest that DNA replication stress induced by a nucleoside analog-type chemotherapeutic drug triggers tumor cytotoxicity by determining tumor cell fate according to p53 status.
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Yuki Kataoka (add twitter)
Makoto Iimori (add twitter)
Ryo Fujisawa (edit)
Tomomi Morikawa-Ichinose (add twitter)
Shinichiro Niimi (add twitter)
Takeshi Wakasa (add twitter)
Hiroshi Saeki (add twitter)
Eiji Oki (add twitter)
Daisuke Miura (edit)
Toshiki Tsurimoto (add twitter)
Yoshihiko Maehara (add twitter)
Hiroyuki Kitao (add twitter)
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Cancer Biology

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09/13/19 07:00AM
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