α-Ketoglutarate-Activated NF-κB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development

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.