Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxidant ascorbate mismatch repair-deficient human colon cancer cells
Suppression of spontaneous and hydrogen peroxide-induced mutagenesis by the antioxidant ascorbate mismatch repair-deficient human colon cancer cells
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DOI：
10.1093/carcin/22.10.1709
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发表时间：
2001-10-01
期刊：
影响因子：
4.7
通讯作者：
Skopek, TR
中科院分区：
文献类型：
--
作者：
Glaab, WE;Hill, RB;Skopek, TR
与错配修复缺陷（MMR）相关的基因组不稳定性在肿瘤发生中起着关键作用。在这里，我们研究了氧化损伤的贡献，这种不稳定性在MMR缺陷细胞。与H2 O2治疗产生较少的细胞毒性MMR缺陷的细胞比那些精通MMR，支持MMR在识别和/或处理氧化损伤的作用。此外，在抗氧化剂抗坏血酸（500 μ M）的存在下，MMR缺陷细胞的生长降低了次黄嘌呤-鸟嘌呤磷酸核糖转移酶（HPRT）位点的自发突变率高达50%，并降低了微卫星不稳定性30%。抗坏血酸也能显著抑制外源H2 O2诱导HPRT突变体。总的来说，这些结果表明，（i）氧化损伤显着有助于自发突变表型的MMR缺陷的细胞，（ii）这种损害可能会选择MMR缺陷的细胞，由于其增加抵抗细胞杀伤和（iii）饮食抗氧化剂可能有助于抑制突变表型和导致的致癌性与受损的MMR的个人。
Genomic instability associated with deficiencies in mismatch repair (MMR) plays a critical role in tumorigenesis. Here we have investigated the contribution of oxidative damage to this instability in MMR-defective cells. Treatment with H2O2 produced less cytotoxicity in MMR-deficient cells than in those proficient in MMR, supporting a role for MMR in the recognition and/or processing of oxidative damage. Additionally, growth of MMR-defective cells in the presence of the antioxidant ascorbate (500 muM) reduced the spontaneous mutation rate at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus by up to 50% and reduced microsatellite instability by 30%. Induction of HPRT mutants by exogenously added H2O2 was also significantly suppressed by ascorbate. Collectively, these results suggest that (i) oxidative damage contributes significantly to the spontaneous mutator phenotype in MMR-defective cells, (ii) this damage may select for MMR-deficient cells due to their increased resistance to cell killing and (iii) dietary antioxidants may help to suppress the mutator phenotype and resulting carcinogenesis in individuals with compromised MMR.