Molecular cell, 2019-10, Vol.76 (1), p.148-162.e7
2019
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- Autor(en) / Beteiligte
- Titel
- α-Ketoglutarate-Activated NF-κB Signaling Promotes Compensatory Glucose Uptake and Brain Tumor Development
- Ist Teil von
- Molecular cell, 2019-10, Vol.76 (1), p.148-162.e7
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •GDH1 is phosphorylated at S384 and interacts with IKK complex under low glucose•GDH1-produced α-KG binds to and activates IKKβ and NF-κB signaling•α-KG-activated NF-κB promotes compensatory glucose uptake and tumor cell survival•GDH1 S384 phosphorylation correlates with grades and prognosis of GBM patients Cancer cells often rewire their metabolic pathways for adaption to nutrient deficiency within tumors. Wang et al. demonstrate here that GDH1 interacts with IKK complex and provides a local source of α-KG, which directly activates IKKβ and NF-κB signaling, thereby promoting glucose uptake, tumor cell survival, and brain tumor development.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1097-2765eISSN: 1097-4164DOI: 10.1016/j.molcel.2019.07.007Titel-ID: cdi_proquest_miscellaneous_2280539317
- Format
- –
- Schlagworte
- Adolescent, Adult, Aged, Aged, 80 and over, Animals, Brain Neoplasms - genetics, Brain Neoplasms - metabolism, Brain Neoplasms - pathology, Cell Line, Tumor, Cell Proliferation, Cell Survival, Child, Energy Metabolism, Female, GDH1, Gene Expression Regulation, Neoplastic, Glioblastoma - genetics, Glioblastoma - metabolism, Glioblastoma - pathology, Glucose - deficiency, Glucose - metabolism, Glucose Transporter Type 1 - genetics, Glucose Transporter Type 1 - metabolism, Glutamate Dehydrogenase - genetics, Glutamate Dehydrogenase - metabolism, HEK293 Cells, Humans, I-kappa B Kinase - genetics, I-kappa B Kinase - metabolism, Ketoglutaric Acids - metabolism, Male, Mice, Inbred BALB C, Mice, Nude, Middle Aged, Neoplasm Grading, NF-kappa B - genetics, NF-kappa B - metabolism, NF-κB, Phosphorylation, Signal Transduction, Transcription Factor RelA - genetics, Transcription Factor RelA - metabolism, tumorigenesis, Young Adult, α-ketoglutarate