MBD4 frameshift mutation caused by DNA mismatch repair deficiency enhances cytotoxicity by trifluridine, an active antitumor agent of TAS-102, in colorectal cancer cells.
MBD4 frameshift mutation caused by DNA mismatch repair deficiency enhances cytotoxicity by trifluridine, an active antitumor agent of TAS-102, in colorectal cancer cells.
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DOI：
10.18632/oncotarget.22484
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发表时间：
2018-02-20
期刊：
影响因子：
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通讯作者：
Sugimoto K
中科院分区：
文献类型：
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作者：
Suzuki S;Iwaizumi M;Yamada H;Sugiyama T;Hamaya Y;Furuta T;Kanaoka S;Sugimura H;Miyajima H;Osawa S;Carethers JM;Sugimoto K
Trifluridine是TAS-102的活性抗肿瘤成分，类似于5-氟尿嘧啶。虽然据报道，表现出错配修复（MMR）缺陷的晚期结直肠癌（CRC）患者不能从基于5-氟尿嘧啶的化疗中获益，并且我们之前报道过截断的甲基- cpg结合结构域蛋白4 （MBD4）增强了5-氟尿嘧啶在MMR缺陷的CRC细胞中的细胞毒性，但关于MMR缺陷对CRC中三氟尿嘧啶细胞毒性的影响知之甚少。我们研究了三氟定是否以DNA核磁共振依赖的方式诱导细胞毒性，并评估了截断的MBD4如何改变三氟定的细胞毒性。我们利用人结直肠癌细胞系HCT116 （hmlh1缺陷细胞）和HCT116+ch3 （hmlh1恢复细胞），比较它们对三氟吡啶的敏感性。建立5-氟尿嘧啶难治性hmlh1缺陷细胞，分析三氟吡啶的细胞毒性。最后，我们建立了截断过表达的MBD4结直肠癌细胞系，并比较了三氟啶的敏感性。HCT116和HCT116+ch3对三氟吡啶的敏感性具有可比性。用三氟吡啶处理的5-氟尿嘧啶难治性hmlh1缺陷细胞显示出与非5-氟尿嘧啶难治性细胞相同或更高的敏感性。此外，MBD4tru细胞对三氟啶的敏感性高于对照细胞。结论：在DNA MMR状态和5-氟尿嘧啶难解条件下，三氟定诱导细胞毒性，MBD4移码突变增强了三氟定的细胞毒性。
Trifluridine is an active antitumor component of TAS-102 that resembles 5-fluorouracil. Although patients with advanced colorectal cancer (CRC) exhibiting a mismatch repair (MMR) deficiency reportedly do not benefit from 5-fluorouracil-based chemotherapy and we previously reported that truncated methyl-CpG binding domain protein 4 (MBD4) enhances 5-fluorouracil cytotoxicity in MMR-deficient CRC cells, little is known regarding the effect of MMR deficiency on trifluridine cytotoxicity in CRC. We investigated whether trifluridine induces cytotoxicity in a DNA MMR-dependent manner and evaluated how truncated MBD4 alters trifluridine cytotoxicity. We utilized the human CRC cell lines HCT116 (hMLH1-deficient cells) and HCT116+ch3 (hMLH1-restored cells) and compared their sensitivities to trifluridine. And we established 5-fluorouracil-refractory hMLH1-deficient cells and analyzed trifluridine cytotoxicity. Finally, we established truncated MBD4 overexpressed CRC cell lines, and compared trifluridine sensitivity. The sensitivities of HCT116 and HCT116+ch3 to trifluridine were comparable. 5-Fluorouracil-refractory hMLH1-deficient cells treated with trifluridine showed an equal or greater sensitivity than non-5-fluorouracil-refractory cells. Moreover, MBD4tru cells were more sensitive than the control cells to trifluridine.Conclusions: Trifluridine induces cytotoxicity independently of the DNA MMR status as well as under 5-fluorouracil-refractory conditions, and the MBD4 frameshift mutation enhances trifluridine cytotoxicity.