De novo synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues
De novo synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues
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DOI：
10.1074/jbc.ra119.008743
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发表时间：
2019-09-06
影响因子：
4.8
通讯作者：
Lane, Andrew N.
中科院分区：
文献类型：
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作者：
Fan, Teresa W. M.;Bruntz, Ronald C.;Lane, Andrew N.
核苷酸合成对于增殖细胞是必不可少的，但从头生物合成的优选前体在人类癌症组织中没有定义。我们采用多重稳定同位素分辨代谢组学来追踪[C-13（6）]葡萄糖、D-2-甘氨酸、[C-13（2）]甘氨酸和D-3-丝氨酸在非小细胞肺癌（NSCLC）患者新鲜切除的癌性和匹配的非癌性肺组织中代谢为嘌呤核苷酸的情况，并在体外将代谢与已建立的NSCLC PC 9和A549细胞系进行比较。令人惊讶的是，[C-13（6）]葡萄糖是人NSCLC组织中嘌呤合成的最佳碳源，而来自同一患者的非癌肺组织显示出较低的有丝分裂指数和MYC表达。我们还观察到，D-3-丝氨酸优先纳入嘌呤环的D-2-甘氨酸在组织和细胞系。MYC抑制减弱了[C-13（6）]葡萄糖、D-3-丝氨酸和[C-13（2）]甘氨酸掺入嘌呤，并降低了PC 9细胞的增殖，但在A549细胞中没有。使用详细的动力学模型，我们表明，首选使用葡萄糖作为碳源的嘌呤环合成在NSCLC组织涉及细胞质激活/区室化的葡萄糖-丝氨酸途径和增强的反向一碳通量，减弱外源性丝氨酸纳入嘌呤。我们的研究结果还表明，从头核苷酸合成的底物之间的癌细胞系和新鲜的人肺癌组织有很大的不同，后者更喜欢葡萄糖外源丝氨酸或甘氨酸，但不是前者。当靶向一碳代谢用于癌症治疗时，应考虑人类癌症组织中嘌呤合成中底物利用的这种差异。
Nucleotide synthesis is essential to proliferating cells, but the preferred precursors for de novo biosynthesis are not defined in human cancer tissues. We have employed multiplexed stable isotope-resolved metabolomics to track the metabolism of [C-13(6)]glucose, D-2-glycine, [C-13(2)]glycine, and D-3-serine into purine nucleotides in freshly resected cancerous and matched noncancerous lung tissues from nonsmall cell lung cancer (NSCLC) patients, and we compared the metabolism with established NSCLC PC9 and A549 cell lines in vitro. Surprisingly, [C-13(6)] glucose was the best carbon source for purine synthesis in human NSCLC tissues, in contrast to the noncancerous lung tissues from the same patient, which showed lower mitotic indices and MYC expression. We also observed that D-3-Ser was preferentially incorporated into purine rings over D-2-glycine in both tissues and cell lines. MYC suppression attenuated [C-13(6)] glucose, D-3-serine, and [C-13(2)] glycine incorporation into purines and reduced proliferation in PC9 but not in A549 cells. Using detailed kinetic modeling, we showed that the preferred use of glucose as a carbon source for purine ring synthesis in NSCLC tissues involves cytoplasmic activation/compartmentation of the glucose-to-serine pathway and enhanced reversed one-carbon fluxes that attenuate exogenous serine incorporation into purines. Our findings also indicate that the substrate for de novo nucleotide synthesis differs profoundly between cancer cell lines and fresh human lung cancer tissues; the latter preferred glucose to exogenous serine or glycine but not the former. This distinction in substrate utilization in purine synthesis in human cancer tissues should be considered when targeting one-carbon metabolism for cancer therapy.