摘要

Cancer cells metabolize different energy sources to generate biomass rapidly. The purine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. However, very little was known about the regulatory mechanisms of purine metabolism in hepatocellular carcinoma (HCC). We explored the role of dual-specificity tyrosine (Y) phosphorylation-regulated kinase 3 (Dyrk3) in HCC metabolism. Dyrk3 was significantly down-regulated in HCC compared with normal controls. Its introduction in HCC cells markedly suppressed tumor growth and metastasis in xenograft tumor models. Mass spectrometric analysis of metabolites suggests that the effect of Dyrk3 on HCC occurred at least partially through down-regulating purine metabolism, as evidenced by the fact that inhibiting purine synthesis reverted the HCC progression mediated by the loss of Dyrk3. We further provide evidence that this action of Dyrk3 knockdown requires nuclear receptor coactivator 3 (NCOA3), which has been shown to be a coactivator of activating transcription factor 4 (ATF4) to target purine pathway genes for transcriptional activation. Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. However, the phosphorylation-resistant NCOA3-S1330A mutant has the opposite effect. Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop. Importantly, levels of Dyrk3 and phospho-NCOA3-S1330 inversely correlate with the expression of ATF4 in human HCC specimens. Conclusion: Our findings not only illustrate a function of Dyrk3 in reprograming HCC metabolism by negatively regulating NCOA3/ATF4 transcription factor complex but also identify NCOA3 as a phosphorylation substrate of Dyrk3, suggesting the Dyrk3/NCOA3/ATF4 axis as a potential candidate for HCC therapy.

译文

癌细胞代谢不同的能源以快速产生生物质。嘌呤生物合成途径最近被认为是这些过程中代谢中间体的重要来源。然而,关于肝细胞肝癌 (HCC) 中嘌呤代谢的调节机制知之甚少。我们探讨了双重特异性酪氨酸 (Y) 磷酸化调节激酶 3 (Dyrk3) 在肝癌代谢中的作用。Dyrk3 在肝癌中与正常对照相比显著下调。它在肝癌细胞中的引入显著抑制了异种移植肿瘤模型中的肿瘤生长和转移。代谢物的质谱分析表明 Dyrk3 对肝癌的影响至少部分是通过下调嘌呤代谢发生的, 事实证明,抑制嘌呤合成恢复 dyrk3 的损失介导的肝癌进展。我们进一步提供证据证明 Dyrk3 击倒的作用需要核受体辅激活因子 3 (NCOA3),它已被证明是激活转录因子 4 (ATF4) 的辅激活因子靶向嘌呤途径基因进行转录激活。从机制上讲,Dyrk3 在 Ser-1330 直接磷酸化 NCOA3,破坏其与 ATF4 的结合,从而导致 ATF4 转录活性的抑制。然而,磷酸化抗性 NCOA3-S1330A 突变体具有相反的效果。有趣的是,Dyrk3 的启动子活性被 ATF4 负调控,表明了一个双负反馈回路。重要的是,Dyrk3 和 phospho-NCOA3-S1330 水平与人类肝癌标本中 ATF4 的表达呈负相关。结论: 我们的发现不仅说明了 Dyrk3 通过负调节 NCOA3/ATF4 转录因子复合物在重编程肝癌代谢中的功能,而且还确定 NCOA3 是 Dyrk3 的磷酸化底物, 提示 Dyrk3/NCOA3/ATF4 轴是肝癌治疗的潜在候选者。

Purine

内分泌 有机化合物 临床研究术语
概述  :  

嘌呤是一种杂环芳族有机化合物,由与咪唑环稠合的嘧啶环组成,它是水溶性的。嘌呤还因其更广泛的分子种类而得名,嘌呤包括取代的嘌呤及其互变异构体。它们是自然界中最广泛存在的含氮杂环。嘌呤在肉类和肉类产品中特别是在肝脏和肾脏等内部器官中含量很高,植物性饮食的嘌呤含量低。 属性 嘌呤既是一种非常弱的酸(pK 为2.39),又是一种较弱的碱(pK 为8.93)。如果溶解在纯水中,pH值将介于这两个pKa值之间。 功能

purine   英/'pjʊəriːn/

释    义   n. [有化] 嘌呤(四氮杂茚,尿杂环);咖啡碱

例    句   But more interestingly, the researchers found three nucleobase-related molecules: purine, 2, 6-diaminopurine, and 6, 8-diaminopurine.但更有趣的是,研究人员发现了三个碱基相关的分子:嘌呤,2,6 -,6,8 – 二 氨基嘌呤。

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