Autophagy prolongs survival after NFκB inhibition in B-cell lymphomas.

Autophagy allows cells to survive under conditions of nutrient deprivation. We have demonstrated that autophagy inhibitors are synthetically lethal with NFκB inhibitors in B-cell lymphomas because the NFκB pathway promotes survival by increasing glucose import. When NFκB is inhibited in B-cell lymphoma, glucose import decreases and cells become sensitive to perturbations in mitochondrial metabolism and autophagy. Thus, combined inhibition of autophagy and NFκB drives cells into metabolic crisis accelerating cell death.

IKKß 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-κB-kinase ß (IKKß) induced glucose transporter-1 (GLUT1) membrane trafficking in both viral and spontaneous B-cell lymphomas. IKKß induced AKT activity, whereas IKKß-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.