DNA Replication Stress Induced by Trifluridine Determines Tumor Cell Fate According to p53 Status
DNA Replication Stress Induced by Trifluridine Determines Tumor Cell Fate According to p53 Status
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DOI：
10.1158/1541-7786.mcr-19-1051
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发表时间：
2020-09-01
影响因子：
5.2
通讯作者：
Kitao, Hiroyuki
中科院分区：
文献类型：
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作者：
Kataoka, Yuki;Iimori, Makoto;Kitao, Hiroyuki
DNA复制应激(DRS)是基因组不稳定的主要原因，是肿瘤发生和恶性进展的驱动因素。核苷类似物类化疗药物在肿瘤细胞中引入DNA损伤并加剧DRS。然而，这些药物的抗肿瘤作用的潜在机制还不完全清楚。在这里，我们证明了氟代胸苷类似物三氟尿苷(FTD)，化疗药物氟尿嘧啶/替吡啶的活性成分，通过作为低效的脱氧核糖核苷酸三磷酸来源(FTD三磷酸)和模板DNA链中的障碍碱(三氟胸苷)，延迟了人类复制DNA聚合酶的DNA合成，从而导致了DRS。在细胞中，FTD降低dNTP池中的胸苷三磷酸水平，增加FTD三磷酸水平，导致S时相DRS诱导的细胞反应被激活。此外，复制蛋白A包被的单链DNA与FANCD2结合，并在肿瘤细胞完成S期后积聚。最后，FTD通过跳过有丝分裂诱导细胞衰老，激活了p53-p21通路，抑制了肿瘤细胞的生长。相反，失去野生型P53的肿瘤细胞通过异常的晚期有丝分裂和严重损害姐妹染色单体的分离而经历了凋亡细胞死亡。这些结果表明，核苷类似物化疗药物诱导的DRS通过根据P53状态引导肿瘤细胞走向细胞衰老或凋亡细胞死亡来抑制肿瘤生长，而与P53状态无关。
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 wildtype 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 analoguetype 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.