Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2.
Myc promotes glutaminolysis in human neuroblastoma through direct activation of glutaminase 2.
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Myc 通过直接激活谷氨酰胺酶 2 促进人神经母细胞瘤中的谷氨酰胺分解。
DOI：
10.18632/oncotarget.5821
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发表时间：
2015-12-01
期刊：
影响因子：
--
通讯作者：
Qing G
中科院分区：
文献类型：
--
作者：
Xiao D;Ren P;Su H;Yue M;Xiu R;Hu Y;Liu H;Qing G
谷氨酰胺通过谷氨酰胺酶1（GLS 1，也称为GLS）和GLS 2脱酰胺为谷氨酸是谷氨酰胺水解和谷胱甘肽（GSH）生物合成的重要步骤。然而，癌细胞调节谷氨酰胺催化剂的机制在很大程度上仍然未知。我们在这里报告，N-Myc，一个必不可少的Myc家族成员，促进谷氨酰胺转化为谷氨酸在MYCN扩增的神经母细胞瘤细胞直接激活GLS 2，但不是GLS 1，转录。GLS 2功能的消除深刻地抑制了多巴胺的分解，这可能是由于硫氧还蛋白相互作用蛋白（TXNIP）的激活，导致有氧糖酵解的反馈抑制，显着降低细胞增殖和存活在体外和体内。此外，与非扩增的神经母细胞瘤相比，MYCN扩增的神经母细胞瘤中GLS 2表达显著升高，与不利的患者生存相关。总的来说，这些结果揭示了一种新的机制，解释了代谢异质性的背景依赖性调节，揭示了Myc，GLS 2和肿瘤代谢之间以前未被怀疑的联系。
Deamidation of glutamine to glutamate by glutaminase 1 (GLS1, also called GLS) and GLS2 is an essential step in both glutaminolysis and glutathione (GSH) biosynthesis. However, mechanisms whereby cancer cells regulate glutamine catabolism remains largely unknown. We report here that N-Myc, an essential Myc family member, promotes conversion of glutamine to glutamate in MYCN-amplified neuroblastoma cells by directly activating GLS2, but not GLS1, transcription. Abrogation of GLS2 function profoundly inhibited glutaminolysis, which resulted in feedback inhibition of aerobic glycolysis likely due to thioredoxin-interacting protein (TXNIP) activation, dramatically decreasing cell proliferation and survival in vitro and in vivo. Moreover, elevated GLS2 expression is significantly elevated in MYCN-amplified neuroblastomas in comparison with non-amplified ones, correlating with unfavorable patient survival. In aggregate, these results reveal a novel mechanism deciphering context-dependent regulation of metabolic heterogeneities, uncovering a previously unsuspected link between Myc, GLS2 and tumor metabolism.