ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.
ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.
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DOI：
10.1016/j.ccr.2012.09.021
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发表时间：
2012-11-13
期刊：
影响因子：
50.3
通讯作者：
Simon MC
中科院分区：
文献类型：
--
作者：
Qing G;Li B;Vu A;Skuli N;Walton ZE;Liu X;Mayes PA;Wise DR;Thompson CB;Maris JM;Hogarty MD;Simon MC
致癌性Myc改变线粒体代谢，使其依赖于外源性谷氨酰胺（Gln）的细胞存活。因此，Gln剥夺通过未知的机制选择性地诱导MYC过表达细胞的凋亡。使用MYCN扩增的神经母细胞瘤作为模型，我们鉴定了Gln-饥饿细胞的执行者是TRB 3，NOXA和TRB 3。MYC转化细胞中的Gln耗尽通过ATF 4依赖性但不依赖于p53的PUMA和NOXA诱导来诱导细胞凋亡。MYC转化的细胞依赖于谷氨酸-草酰乙酸转氨酶和谷氨酸脱氢酶来维持Gln稳态并抑制凋亡。因此，ATF 4激动剂或氨解抑制剂在体外有效地诱导细胞凋亡并在体内抑制肿瘤生长。这些结果揭示了Myc使细胞对凋亡敏感的机制，并验证了ATF 4激动剂和谷氨酰胺代谢抑制剂作为潜在的Myc选择性癌症治疗剂。
Oncogenic Myc alters mitochondrial metabolism, making it dependent on exogenous glutamine (Gln) for cell survival. Accordingly, Gln deprivation selectively induces apoptosis in MYC-overexpressing cells via unknown mechanisms. Using MYCN-amplified neuroblastoma as a model, we identify PUMA, NOXA and TRB3 as executors of Gln-starved cells. Gln depletion in MYC-transformed cells induces apoptosis through ATF4-dependent, but p53-independent, PUMA and NOXA induction. MYC-transformed cells depend on both glutamate-oxaloacetate transaminase and glutamate dehydrogenase to maintain Gln homeostasis and suppress apoptosis. Consequently, either ATF4 agonists or glutaminolysis inhibitors potently induce apoptosis in vitro and inhibit tumor growth in vivo. These results reveal mechanisms whereby Myc sensitizes cells to apoptosis and validate ATF4 agonists and inhibitors of Gln metabolism as potential Myc-selective cancer therapeutics.
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影响因子：
50.3
作者：
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