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DNA replication stress induced by trifluridine determines tumor cell fate according to p53 status
Molecular Cancer Research ( IF 5.2 ) Pub Date : 2020-05-28 , DOI: 10.1158/1541-7786.mcr-19-1051
Yuki Kataoka 1, 2 , Makoto Iimori 1 , Ryo Fujisawa 3 , Tomomi Morikawa-Ichinose 4 , Shinichiro Niimi 5 , Takeshi Wakasa 1, 2 , Hiroshi Saeki 6, 7 , Eiji Oki 6 , Daisuke Miura 4, 8 , Toshiki Tsurimoto 3 , Yoshihiko Maehara 5, 6, 9 , Hiroyuki Kitao 1, 5
Affiliation  

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.

中文翻译:

三氟尿苷诱导的 DNA 复制应激根据 p53 状态决定肿瘤细胞的命运

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。核苷类似物类型的化疗药物会在肿瘤细胞中引入 DNA 损伤并加剧 DRS。然而,这些药物抗肿瘤作用的潜在机制尚不完全清楚。在这里,我们展示了氟化胸苷类似物三氟尿苷 (FTD),化疗药物三氟尿苷/tipiracil 的活性成分,通过充当低效的脱氧核糖核苷酸三磷酸源 (FTD 三磷酸) 和障碍来延迟人类复制 DNA 聚合酶的 DNA 合成模板 DNA 链中的碱基(三氟胸腺嘧啶),导致 DRS。在细胞中,FTD 降低了 dNTP 库中的胸苷三磷酸水平并增加了 FTD 三磷酸水平,导致在 S 期激活 DRS 诱导的细胞反应。此外,复制蛋白 A 包被与 FancD2 相关的单链 DNA,并在肿瘤细胞完成 S 期后积累。最后,FTD 激活 p53-p21 通路并通过有丝分裂跳跃诱导细胞衰老来抑制肿瘤细胞生长。相比之下,失去野生型 p53 的肿瘤细胞通过异常晚期有丝分裂经历凋亡细胞死亡,姐妹染色单体的分离严重受损。这些结果表明,核苷类似物型化疗药物诱导的 DRS 通过根据 p53 状态将肿瘤细胞命运导向细胞衰老或凋亡细胞死亡,从而抑制肿瘤生长,而不管 p53 状态如何。含义:
更新日期:2020-05-28
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