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 损伤介质 6-Thio-2'-Deoxyguanosine 敏感的生物标志物。


细胞膜转运蛋白促进核碱基和核苷的通过以进行核苷酸合成和代谢，并且对于抗癌药物治疗中使用的核苷类似物的递送很重要。在这里，我们研究了细胞膜转运蛋白是否参与细胞摄取核苷类似物 DNA 损伤介质 6-硫代-2'-脱氧鸟苷 (6-thio-dG)。大量非小细胞肺癌 (NSCLC) 细胞系（77 个中的 73 个）对 6-硫代-dG 敏感；只有四种 NSCLC 系对 6-硫代-dG 具有耐药性。通过微阵列和 RNA 测序进行分析时，耐药 NSCLC 细胞系聚集在一起，为可能对 6-thio-dG 无反应的患者提供了分子特征。溶质载体家族 43 A3 (SLC43A3)（一种平衡核碱基转运蛋白）的显着下调被确定为该分子抗性特征的候选者。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 损伤介质 6-硫代-2'-脱氧鸟苷具有抗性的生物标志物。