Abstract
All cancer cells require increased nutrient uptake to support proliferation. In this study, we investigated the signals that govern glucose uptake in B-cell lymphomas and determined that the inhibitor of NF-κB-kinase β (IKKβ) induced glucose transporter-1 (GLUT1) membrane trafficking in both viral and spontaneous B-cell lymphomas. IKKβ induced AKT activity, whereas IKKβ-driven NF-κB transcription was required for GLUT1 surface localization downstream of AKT. Activated NF-κB promoted AKT-mediated phosphorylation of the GLUT1 regulator, AKT substrate of 160kD (AS160), but was not required for AKT phosphorylation of the mTOR regulator Tuberous Sclerosis 2 (TSC2). In Epstein-Barr virus-transformed B cells, NF-κB inhibition repressed glucose uptake and induced caspase-independent cell death associated with autophagy. After NF-κB inhibition, an alternate carbon source ameliorated both autophagy and cell death, whereas autophagy inhibitors specifically accelerated cell death. Taken together, the results indicate that NF-κB signaling establishes a metabolic program supporting proliferation and apoptosis resistance by driving glucose import.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Apoptosis / genetics
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Autophagy / genetics
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Caspases / metabolism
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Cell Death / genetics
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Cell Growth Processes / genetics
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Cell Membrane / genetics
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Cell Membrane / metabolism
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Cell Survival / genetics
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Gene Expression Regulation, Neoplastic
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Glucose Transporter Type 1 / genetics
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Glucose Transporter Type 1 / metabolism*
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Herpesvirus 4, Human / genetics
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Herpesvirus 4, Human / metabolism
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Humans
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I-kappa B Kinase / biosynthesis
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I-kappa B Kinase / genetics*
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I-kappa B Kinase / metabolism
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Lymphoma, B-Cell / genetics*
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Lymphoma, B-Cell / metabolism
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / biosynthesis
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NF-kappa B / genetics*
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NF-kappa B / metabolism
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Phosphorylation / genetics
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Protein Transport
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Proto-Oncogene Proteins c-akt / biosynthesis
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Proto-Oncogene Proteins c-akt / genetics*
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction / genetics
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TOR Serine-Threonine Kinases / metabolism
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Tuberous Sclerosis Complex 2 Protein
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / metabolism
Substances
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Glucose Transporter Type 1
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NF-kappa B
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SLC2A1 protein, human
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TSC2 protein, human
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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MTOR protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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I-kappa B Kinase
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IKBKB protein, human
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Caspases