The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma.
The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma.
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DOI：
10.1016/j.ccell.2018.04.002
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发表时间：
2018-05-14
期刊：
影响因子：
50.3
通讯作者：
Shackelford DB
中科院分区：
文献类型：
--
作者：
Momcilovic M;Bailey ST;Lee JT;Fishbein MC;Braas D;Go J;Graeber TG;Parlati F;Demo S;Li R;Walser TC;Gricowski M;Shuman R;Ibarra J;Fridman D;Phelps ME;Badran K;St John M;Bernthal NM;Federman N;Yanagawa J;Dubinett SM;Sadeghi S;Christofk HR;Shackelford DB
改变的代谢是癌症生长的标志，形成了发展代谢疗法作为癌症治疗的概念基础。我们对肺鳞状细胞癌（SCC）进行了体内代谢谱分析和分子分析，以确定治疗靶点的代谢节点。肺SCC通过GSK 3 α/β信号通路适应慢性mTOR抑制和糖酵解抑制，该信号通路上调β-内酰胺酶解。磷酸化-GSK 3 α/β蛋白水平可预测对单一疗法mTOR抑制的响应，而与转氨酶抑制剂CB-839的组合治疗有效地克服了疗法抗性。此外，我们在广泛的高代谢人类肿瘤中鉴定了保守的代谢特征，其可以预测患者结果和对靶向mTOR和谷氨酰胺酶的组合代谢疗法的反应。
Altered metabolism is a hallmark of cancer growth, forming the conceptual basis for development of metabolic therapies as cancer treatments. We performed in vivo metabolic profiling and molecular analysis of lung squamous cell carcinoma (SCC) to identify metabolic nodes to therapeutically target. Lung SCCs adapt to chronic mTOR inhibition and suppression of glycolysis through the GSK3α/β signaling pathway which upregulates glutaminolysis. Phospho-GSK3α/β protein levels are predictive of response to single therapy mTOR inhibition while combinatorial treatment with the glutaminase inhibitor CB-839 effectively overcomes therapy resistance. In addition, we identified a conserved metabolic signature in a broad spectrum of hypermetabolic human tumors that may be predictive of patient outcome and response to combined metabolic therapies targeting mTOR and glutaminase.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
11.2
作者：
Momcilovic M;McMickle R;Abt E;Seki A;Simko SA;Magyar C;Stout DB;Fishbein MC;Walser TC;Dubinett SM;Shackelford DB
通讯作者：
Shackelford DB
影响因子：
16.6
作者：
Goodwin J;Neugent ML;Lee SY;Choe JH;Choi H;Jenkins DMR;Ruthenborg RJ;Robinson MW;Jeong JY;Wake M;Abe H;Takeda N;Endo H;Inoue M;Xuan Z;Yoo H;Chen M;Ahn JM;Minna JD;Helke KL;Singh PK;Shackelford DB;Kim JW
通讯作者：
Kim JW
影响因子：
64.8
作者：
Metallo, Christian M.;Gameiro, Paulo A.;Bell, Eric L.;Mattaini, Katherine R.;Yang, Juanjuan;Hiller, Karsten;Jewell, Christopher M.;Johnson, Zachary R.;Irvine, Darrell J.;Guarente, Leonard;Kelleher, Joanne K.;Vander Heiden, Matthew G.;Iliopoulos, Othon;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory
影响因子：
64.8
作者：
Ji, Hongbin;Ramsey, Matthew R.;Wong, Kwok-Kin
通讯作者：
Wong, Kwok-Kin