Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism
Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism
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DOI：
10.1016/j.celrep.2019.09.056
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发表时间：
2019-10-29
期刊：
影响因子：
8.8
通讯作者：
Zong, Wei-Xing
中科院分区：
文献类型：
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作者：
Bott, Alex J.;Shen, Jianliang;Zong, Wei-Xing
谷氨酰胺被认为在癌细胞中发挥重要作用，通过谷氨酰胺水解成α -酮戊二酸（aKG），为三羧酸（TCA）循环提供燃料。为了支持这一观点，补充aKG可以恢复谷氨酰胺缺失细胞的生长/存活。然而，胰腺癌通常血管化不良，谷氨酰胺供应有限，这与最近对谷氨酰胺溶解在胰腺癌中的意义的关注一致。在这里，我们发现akg介导的谷氨酰胺缺失胰导管癌（PDAC）细胞的修复需要谷氨酸氨连接酶（GLUL），这种酶负责从头合成谷氨酰胺。缺乏gll的PDAC细胞能够进行TCA循环，但在akg偶联的谷氨酰胺生物合成和随后的氮合成代谢过程中存在缺陷。重要的是，GLUL表达在胰腺癌患者样本和小鼠PDAC模型中升高。GLUL消融抑制Kras（G12D）驱动的小鼠PDAC的发展。因此，gll介导的谷氨酰胺生物合成将TCA循环与氮合成代谢耦合在一起，并在PDAC中发挥关键作用。
Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to alpha-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of Kras(G12D)-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.