Abstract
Cell proliferation is a metabolically demanding process. It requires active reprogramming of cellular bioenergetic pathways towards glucose metabolism to support anabolic growth. NF-κB/Rel transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis, but whether NF-κB regulates the metabolic reprogramming required for cell division during these processes is unknown. Here, we report that NF-κB organizes energy metabolism networks by controlling the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose starvation. The metabolic reorganization that results from NF-κB inhibition overcomes the requirement for tumour suppressor mutation in oncogenic transformation and impairs metabolic adaptation in cancer in vivo. This NF-κB-dependent metabolic pathway involves stimulation of oxidative phosphorylation through upregulation of mitochondrial synthesis of cytochrome c oxidase 2 (SCO2; ref. ). Our findings identify NF-κB as a physiological regulator of mitochondrial respiration and establish a role for NF-κB in metabolic adaptation in normal cells and cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptation, Physiological
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Adenosine Triphosphate / metabolism
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Animals
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Cell Line, Tumor
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Cell Proliferation*
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Cell Respiration*
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Colonic Neoplasms / pathology
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Electron Transport Complex IV / metabolism
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Energy Metabolism*
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Female
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Glucose / deficiency
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Glucose / metabolism
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Glycolysis
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Homeostasis
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Lactic Acid / metabolism
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Mice
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Mice, Knockout
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Mice, Nude
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Mitochondria / metabolism*
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Molecular Chaperones
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Necrosis
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Oxidative Phosphorylation
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Oxygen Consumption
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RNA Interference
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Time Factors
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Transcription Factor RelA / deficiency
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism*
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Transfection
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Tumor Burden
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Up-Regulation
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bcl-2 Homologous Antagonist-Killer Protein / genetics
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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Bak1 protein, mouse
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Bax protein, mouse
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Molecular Chaperones
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RELA protein, human
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Rela protein, mouse
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SCO2 protein, mouse
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Transcription Factor RelA
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Tumor Suppressor Protein p53
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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Lactic Acid
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Adenosine Triphosphate
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Electron Transport Complex IV
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Glucose