IKKβ and NF-κB Transcription Govern Lymphoma Cell Survival through AKT-Induced Plasma Membrane Trafficking of GLUT1

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-kappa B-kinase beta (IKK beta) induced glucose transporter-1 (GLUT1) membrane trafficking in both viral and spontaneous B-cell lymphomas. IKK beta induced AKT activity, whereas IKK beta-driven NF-kappa B transcription was required for GLUT1 surface localization downstream of AKT. Activated NF-kB 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-kB inhibition repressed glucose uptake and induced caspase-independent cell death associated with autophagy. After NF-kB 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-kB signaling establishes a metabolic program supporting proliferation and apoptosis resistance by driving glucose import. Cancer Res; 71(23); 7291-300. (C) 2011 AACR.