AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells
AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells
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AICAr 通过诱导急性淋巴细胞白血病细胞中 NTP 和 dNTP 池失衡来抑制细胞增殖
DOI：
10.1096/fj.201801559rr
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发表时间：
2019-03-01
期刊：
影响因子：
4.8
通讯作者：
Zhou, Bin-Bing S.
中科院分区：
文献类型：
--
作者：
Du, Lijuan;Yang, Fan;Zhou, Bin-Bing S.
研究表明，5-氨基-4-咪唑甲酰胺核苷 (AICAr) 可以抑制儿童急性淋巴细胞白血病 (ALL) 细胞的增殖并诱导细胞凋亡。尽管AICAr可以通过激活AMPK来调节细胞能量代谢，但AICAr的细胞毒性机制仍不清楚。在这里，我们通过使用成簇的规则间隔短回文重复/Cas9系统敲除NALM-6和Reh细胞中的TP53或PRKAA1基因（编码AMPK1），发现AICAr诱导的增殖抑制与AMPK激活无关，而是依赖于p53。核苷酸代谢物的液相色谱-质谱分析表明，AICAr通过上调嘌呤生物合成导致三磷酸腺苷、三磷酸脱氧腺苷和三磷酸脱氧鸟苷水平增加，而由于焦磷酸核糖生成减少，AICAr导致三磷酸胞苷、三磷酸尿苷、三磷酸脱氧胞苷和三磷酸脱氧胸苷水平降低，从而损害了嘧啶生物合成。三磷酸核糖核苷 (NTP) 库失衡抑制了 rRNA 转录效率。此外，脱氧核糖核苷三磷酸 (dNTP) 池失衡会诱导 DNA 复制应激和 DNA 双链断裂，随后导致 ALL 细胞的细胞周期停滞和细胞凋亡。外源尿苷可以通过补充嘧啶来重新平衡 NTP 和 dNTP 池，然后减弱 AICAr 诱导的细胞毒性。我们的数据表明，由 NTP 和 dNTP 库失衡引起的 RNA 转录抑制和 DNA 复制应激可能在 AICAr 介导的 ALL 细胞细胞毒性作用中发挥关键作用，表明 AICAr 在未来 ALL 治疗中的潜在临床应用。 Du, L., Yang, F., Fang, H., Sun, H., Chen, Y., Xu, Y., Li, H., Cheng, L., Zhou, B.-B. S. AICAr 通过诱导急性淋巴细胞白血病细胞中 NTP 和 dNTP 库失衡来抑制细胞增殖。
It has been shown that 5-amino-4-imidazolecarboxamide riboside (AICAr) can inhibit cell proliferation and induce apoptosis in childhood acute lymphoblastic leukemia (ALL) cells. Although AICAr could regulate cellular energy metabolism by activating AMPK, the cytotoxic mechanisms of AICAr are still unclear. Here, we knocked out TP53 or PRKAA1 gene (encoding AMPK1) in NALM-6 and Reh cells by using the clustered regularly interspaced short palindromic repeats/Cas9 system and found that AICAr-induced proliferation inhibition was independent of AMPK activation but dependent on p53. Liquid chromatography-mass spectrometry analysis of nucleotide metabolites indicated that AICAr caused an increase in adenosine triphosphate, deoxyadenosine triphosphate, and deoxyguanosine triphosphate levels by up-regulating purine biosynthesis, while AICAr led to a decrease in cytidine triphosphate, uridine triphosphate, deoxycytidine triphosphate, and deoxythymidine triphosphate levels because of reduced phosphoribosyl pyrophosphate production, which consequently impaired the pyrimidine biosynthesis. Ribonucleoside triphosphate (NTP) pool imbalances suppressed the rRNA transcription efficiency. Furthermore, deoxy-ribonucleoside triphosphate (dNTP) pool imbalances induced DNA replication stress and DNA double-strand breaks, followed by cell cycle arrest and apoptosis in ALL cells. Exogenous uridine could rebalance the NTP and dNTP pools by supplementing pyrimidine and then attenuate AICAr-induced cytotoxicity. Our data indicate that RNA transcription inhibition and DNA replication stress induced by NTP and dNTP pool imbalances might play a key role in AICAr-mediated cytotoxic effects on ALL cells, suggesting a potential clinical application of AICAr in future ALL therapy.Du, L., Yang, F., Fang, H., Sun, H., Chen, Y., Xu, Y., Li, H., Zheng, L., Zhou, B.-B. S. AICAr suppresses cell proliferation by inducing NTP and dNTP pool imbalances in acute lymphoblastic leukemia cells.