OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues
OCTN1 Is a High-Affinity Carrier of Nucleoside Analogues
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DOI：
10.1158/0008-5472.can-16-2548
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发表时间：
2017-04-15
期刊：
影响因子：
11.2
通讯作者：
Sparreboom, Alex
中科院分区：
文献类型：
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作者：
Drenberg, Christina D.;Gibson, Alice A.;Sparreboom, Alex
对用于治疗急性髓性白血病（AML）和其他癌症的异生素核苷的耐药性仍然是临床管理的主要障碍。参与耐药的一个过程是通过核苷转运蛋白进入肿瘤细胞的摄取减少，尽管确切的机制尚不清楚。通过转录组学分析，我们确定麦角硫因转运蛋白OCTN 1（SLC 22 A4; ETT）的低表达强烈预测接受胞苷核苷类似物阿糖胞苷治疗的多个AML患者队列的无事件生存期和总生存期较差。细胞生物学研究证实，OCTN 1介导的阿糖胞苷和各种结构相关的胞苷类似物（如2 '-脱氧胞苷和吉西他滨）的转运是通过一个可饱和的过程发生的，该过程对经典核苷转运蛋白抑制剂双嘧达莫和硝基苄基巯基嘌呤核糖核苷的抑制高度敏感。我们的研究结果具有直接的临床意义，因为所确定的转运系统具有帮助改进策略的潜力，这些策略可以改善多种癌症类型的患者生存率，其中核苷类似物用于癌症治疗。(C)2017年AACR。
Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (SLC22A4; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analogue cytarabine. Cell biological studies confirmed OCTN1-mediated transport of cytarabine and various structurally related cytidine analogues, such as 2'-deoxycytidine and gemcitabine, occurs through a saturable process that is highly sensitive to inhibition by the classic nucleoside transporter inhibitors dipyridamole and nitrobenzylmercaptopurine ribonucleoside. Our findings have immediate clinical implications given the potential of the identified transport system to help refine strategies that could improve patient survival across multiple cancer types where nucleoside analogues are used in cancer treatment. (C) 2017 AACR.