SAMHD1 protects cancer cells from various nucleoside-based antimetabolites.
SAMHD1 protects cancer cells from various nucleoside-based antimetabolites.
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DOI：
10.1080/15384101.2017.1314407
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发表时间：
2017-06-03
期刊：
影响因子：
--
通讯作者：
Schaller T
中科院分区：
文献类型：
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作者：
Herold N;Rudd SG;Sanjiv K;Kutzner J;Bladh J;Paulin CBJ;Helleday T;Henter JI;Schaller T
最近，我们发现无菌α基序和含HD结构域的蛋白1（SAMHD 1）是急性髓细胞白血病（AML）细胞对阿糖胞苷（ara-C）细胞毒性的主要屏障，阿糖胞苷是治疗AML的最重要药物。Ara-C通过经典dNTP合成途径在细胞内转化为ara-CTP，ara-CTP充当SAMHD 1的底物而不是变构激活剂。使用AML小鼠模型，我们在此显示野生型但非催化失活的SAMHD 1降低体内阿糖胞苷治疗功效。扩展SAMHD 1的临床相关底物，我们证明缺乏功能性SAMHD 1基因的THP-1 CRISPR/Cas9细胞显示出对抗代谢物奈拉滨、氟达拉滨、地西他滨、阿糖腺苷、氯法拉滨和曲氟尿苷的敏感性增加。在这个额外的视图中，我们讨论并建立在这些和我们以前报道的发现的基础上，并提出SAMHD 1可能对抗癌化疗中存在的各种核苷类似物抗代谢物具有活性。因此，SAMHD 1可能构成一个有前途的目标，以改善血液学和非血液学恶性肿瘤的广泛治疗。
Recently, we demonstrated that sterile α motif and HD domain containing protein 1 (SAMHD1) is a major barrier in acute myelogenous leukemia (AML) cells to the cytotoxicity of cytarabine (ara-C), the most important drug in AML treatment. Ara-C is intracellularly converted by the canonical dNTP synthesis pathway to ara-CTP, which serves as a substrate but not an allosteric activator of SAMHD1. Using an AML mouse model, we show here that wild type but not catalytically inactive SAMHD1 reduces ara-C treatment efficacy in vivo. Expanding the clinically relevant substrates of SAMHD1, we demonstrate that THP-1 CRISPR/Cas9 cells lacking a functional SAMHD1 gene showed increased sensitivity to the antimetabolites nelarabine, fludarabine, decitabine, vidarabine, clofarabine, and trifluridine. Within this Extra View, we discuss and build upon both these and our previously reported findings, and propose SAMHD1 is likely active against a variety of nucleoside analog antimetabolites present in anti-cancer chemotherapies. Thus, SAMHD1 may constitute a promising target to improve a wide range of therapies for both hematological and non-haematological malignancies.