Cell membrane transporters facilitate the passage of nucleobases and nucleosides for nucleotide synthesis and metabolism, and are important for the delivery of nucleoside analogues used in anticancer drug therapy. Here, we investigated if cell membrane transporters are involved in the cellular uptake of the nucleoside analogue DNA damage mediator 6-thio-2'-deoxyguanosine (6-thio-dG). A large panel of non-small cell lung cancer (NSCLC) cell lines (73 of 77) were sensitive to 6-thio-dG; only four NSCLC lines were resistant to 6-thio-dG. When analyzed by microarray and RNA sequencing, the resistant NSCLC cell lines clustered together, providing a molecular signature for patients that may not respond to 6-thio-dG. Significant downregulation of solute carrier family 43 A3 (SLC43A3), an equilibrative nucleobase transporter, was identified as a candidate in this molecular resistance signature. High levels of SLC43A3 mRNA predicted sensitivity to 6-thio-dG and therefore SLC43A3 could serve as a promising biomarker for 6-thio-dG sensitivity in patients with NSCLC. SIGNIFICANCE: These findings identify a biomarker of resistance to the telomeric DNA damage mediator 6-thio-2'-deoxyguanosine.

中文翻译：

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SLC43A3是对端粒DNA损伤介体6-Thio-2'-Deoxyguanosine敏感的生物标志物。

细胞膜转运蛋白促进核苷酸碱基和核苷通过以进行核苷酸合成和代谢，并且对于抗癌药物治疗中所用核苷类似物的传递非常重要。在这里，我们调查了细胞膜转运蛋白是否参与细胞核苷类似物DNA损伤介导物6-硫代2'-脱氧鸟苷（6-硫代-dG）的摄取。一大批非小细胞肺癌（NSCLC）细胞系（77个中的73个）对6-硫代-dG敏感；仅四个NSCLC系对6-硫代-dG具有抗性。通过微阵列和RNA测序分析时，耐药的NSCLC细胞系聚集在一起，为可能对6-硫代-dG无反应的患者提供分子标记。溶质载体家族43 A3（SLC43A3）（一种平衡的核碱基转运蛋白）显着下调，被鉴定为该分子抗性标记的候选者。高水平的SLC43A3 mRNA预测对6-硫代-dG的敏感性，因此SLC43A3可以作为NSCLC患者6-硫代-dG敏感性的有前途的生物标志物。意义：这些发现确定了对端粒DNA损伤介体6-thio-2'-deoxyguanosine具有抗性的生物标记。