Background We postulate that meningiomas undergo distinct metabolic reprogramming in tumorigenesis and unraveling their metabolic phenotypes provide new therapeutic insights. Glutamine catabolism is key to the growth and proliferation of tumors. Here, we investigated the metabolomics of freshly resected meningiomas and glutamine metabolism in patient-derived meningioma cells. Methods 1H NMR spectroscopy of tumor tissues from meningioma patients was used to differentiate the metabolite profiles of grade-I and grade-II meningiomas. Glutamine metabolism was examined using 13C/15N glutamine tracer, in 5 patient-derived meningioma cells. Results Alanine, lactate, glutamate, glutamine, and glycine were predominantly elevated only in grade-II meningiomas by 74%, 76%, 35%, 75%, and 33%, respectively, with alanine and glutamine levels being statistically significant (P ≤ .02). 13C/15N glutamine tracer experiments revealed that both grade-I and -II meningiomas actively metabolize glutamine to generate various key carbon intermediates including alanine and proline that are necessary for the tumor growth. Also, it is shown that glutaminase (GLS1) inhibitor, CB-839 is highly effective in downregulating glutamine metabolism and decreasing proliferation in meningioma cells. Conclusion Alanine and glutamine/glutamate are mainly elevated in grade-II meningiomas. Grade-I meningiomas possess relatively higher glutamine metabolism providing carbon/nitrogen for the biosynthesis of key nonessential amino acids. GLS1 inhibitor (CB-839) is very effective in downregulating glutamine metabolic pathways in grade-I meningiomas leading to decreased cellular proliferation.

中文翻译：

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人脑膜瘤的氨基酸生物合成需要谷氨酰胺回补

背景我们假设脑膜瘤在肿瘤发生过程中经历了不同的代谢重编程，揭示其代谢表型提供了新的治疗见解。谷氨酰胺分解代谢是肿瘤生长和增殖的关键。在这里，我们研究了新切除的脑膜瘤的代谢组学和患者来源的脑膜瘤细胞中的谷氨酰胺代谢。方法 脑膜瘤患者肿瘤组织的 1H NMR 光谱用于区分 I 级和 II 级脑膜瘤的代谢物谱。使用 13C/15N 谷氨酰胺示踪剂在 5 个患者来源的脑膜瘤细胞中检查谷氨酰胺代谢。结果丙氨酸、乳酸、谷氨酸、谷氨酰胺和甘氨酸仅在 II 级脑膜瘤中显着升高，分别升高 74%、76%、35%、75% 和 33%，丙氨酸和谷氨酰胺水平具有统计学意义 (P ≤ .02)。13C/15N 谷氨酰胺示踪剂实验表明，I 级和 II 级脑膜瘤都积极代谢谷氨酰胺以产生各种关键的碳中间体，包括肿瘤生长所必需的丙氨酸和脯氨酸。此外，显示谷氨酰胺酶 (GLS1) 抑制剂 CB-839 在下调谷氨酰胺代谢和减少脑膜瘤细胞增殖方面非常有效。结论 丙氨酸和谷氨酰胺/谷氨酸主要在Ⅱ级脑膜瘤中升高。I级脑膜瘤具有相对较高的谷氨酰胺代谢，为关键非必需氨基酸的生物合成提供碳/氮。