α-Ketoglutarate-Activated NF-κB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development
α-Ketoglutarate-Activated NF-κB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development
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α-酮戊二酸激活的 NF-kappa B 信号传导促进代偿性葡萄糖摄取和脑肿瘤发展
DOI：
10.1016/j.molcel.2019.07.007
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发表时间：
2019-10-03
期刊：
影响因子：
16
通讯作者：
Yang, Weiwei
中科院分区：
文献类型：
--
作者：
Wang, Xiongjun;Liu, Ruilong;Yang, Weiwei
肿瘤内癌细胞的快速增殖和失调的脉管系统导致有限的营养可及性。癌细胞经常重新调整其代谢途径以适应营养压力，其潜在机制在很大程度上仍然未知。谷氨酸脱氢酶1（GDH 1）是谷氨酸氨解中的关键酶，其将谷氨酸转化为α-酮戊二酸（α-KG）。在这里，我们表明，在低葡萄糖下，GDH 1在丝氨酸（S）384处磷酸化，并与RelA和IKK β相互作用。GDH 1产生的α-KG直接结合并激活IKK β和核因子κ B（NF-κ B B）信号传导，通过上调GLUT 1促进葡萄糖摄取和肿瘤细胞存活，从而加速胶质瘤形成。此外，GDH 1 S384磷酸化与人胶质母细胞瘤的恶性程度和预后相关。我们的发现揭示了α-KG直接调节信号通路的独特作用，揭示了代谢物介导的NF-κ B活化的独特机制，并且还确立了α-KG活化的NF-κ B在脑肿瘤发展中的关键作用。
The rapid proliferation of cancer cells and dysregulated vasculature within the tumor leads to limited nutrient accessibility. Cancer cells often rewire their metabolic pathways for adaption to nutrient stress, and the underlying mechanism remains largely unknown. Glutamate dehydrogenase 1 (GDH1) is a key enzyme in glutaminolysis that converts glutamate to alpha-ketoglutarate (alpha-KG). Here, we show that, under low glucose, GDH1 is phosphorylated at serine (S) 384 and interacts with RelA and IKK beta. GDH1-produced alpha-KG directly binds to and activates IKK beta and nuclear factor kappa B (NF-kappa B) signaling, which promotes glucose uptake and tumor cell survival by upregulating GLUT1, thereby accelerating gliomagenesis. In addition, GDH1 S384 phosphorylation correlates with the malignancy and prognosis of human glioblastoma. Our finding reveals a unique role of alpha-KG to directly regulate signal pathway, uncovers a distinct mechanism of metabolite-mediated NF-kappa B activation, and also establishes the critical role of alpha-KG-activated NF-kappa B in brain tumor development.