GSK3 信号轴调节肺鳞癌中的适应性谷氨酰胺代谢。
The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma.
机构信息
Department of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
出版信息
Cancer Cell. 2018 May 14;33(5):905-921.e5. doi: 10.1016/j.ccell.2018.04.002.
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 for therapeutic targeting. 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.
代谢改变是癌症生长的一个标志，为代谢疗法作为癌症治疗的发展提供了概念基础。我们对肺鳞状细胞癌 (SCC) 进行了体内代谢分析和分子分析，以确定治疗靶点的代谢节点。肺 SCC 通过 GSK3α/β 信号通路适应慢性 mTOR 抑制和糖酵解抑制，上调谷氨酰胺分解。磷酸化-GSK3α/β 蛋白水平可预测对单药 mTOR 抑制的反应，而联合使用谷氨酰胺酶抑制剂 CB-839 可有效克服治疗耐药性。此外，我们在广泛的高代谢人类肿瘤中发现了一个保守的代谢特征，该特征可能预测患者的结局和对靶向 mTOR 和谷氨酰胺酶的联合代谢治疗的反应。
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