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 α-ketoglutarate (α-KG). Here, we show that, under low glucose, GDH1 is phosphorylated at serine (S) 384 and interacts with RelA and IKKβ. GDH1-produced α-KG directly binds to and activates IKKβ and nuclear factor κB (NF-κB) 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 α-KG to directly regulate signal pathway, uncovers a distinct mechanism of metabolite-mediated NF-κB activation, and also establishes the critical role of α-KG-activated NF-κB in brain tumor development.
α-Ketoglutarate-Activated NF-κB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development.
Xiongjun Wang,Ruilong Liu,X. Qu,Hua Yu,Huiying Chu,Yajuan Zhang,Wencheng Zhu,Xueyuan Wu,H. Gao,Bangbao Tao,Wenfeng Li,Ji Liang,Guohui Li,Weiwei Yang
Published 2019 in Molecules and Cells
ABSTRACT
PUBLICATION RECORD
- Publication year
2019
- Venue
Molecules and Cells
- Publication date
2019-10-03
- Fields of study
Biology, Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
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