Tumor and Stem Cell Biology IKKb and NF-kB Transcription Govern Lymphoma Cell Survival throughAKT-InducedPlasmaMembrane 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-kB-kinase b (IKKb) induced glucose transporter-1 (GLUT1) membrane trafficking in both viral and spontaneous B-cell lymphomas. IKKb induced AKT activity, whereas IKKb-driven NF-kB 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); 1–10. 2011 AACR.