TY  - THES
T1  - The role of NF?B in glucose import and survival of B-cell lymphomas
A1  - Sommermann,Thomas
Y1  - 2012/04/27
N2  - Continuously proliferating cells must exhibit high levels of nutrient uptake in order to support biosynthetic pathways. Most cancer cells exhibit elevated glucose import and consumption rates when compared with normal tissue. This work investigates the signals that govern glucose uptake in B-cell lymphomas. The experiments presented provide evidence that the NF?B pathway controls glucose import via GLUT1 membrane trafficking in both viral and spontaneous B-cell lymphomas. To promote GLUT1 translocation the NF?B pathway activates the signaling cascade from PI3K to GLUT1 plasma membrane translocation at two distinct points. First, the NF?B-stimulating I?B-kinase ? (IKK?) supported Phosphatidylinositol-3-kinase (PI3K) driven AKT activity. Second, NF?B-induced transcription was required for GLUT1 surface localization downstream of AKT, by licensing AKT-mediated phosphorylation of the GLUT1 regulator, AKT Substrate of 160kD (AS160). The requirement for NF?B was specific for productive AKT/AS160 interaction, as AKT phosphorylation of the mammalian target of Rapamycin (mTOR) regulator Tuberous Sclerosis 2 (TSC2) was independent of NF?B.
In Epstein Barr virus (EBV) transformed B-cells the NF?B pathway was essential to sustain energy homeostasis and survival. Inhibition of NF?B-induced transcription repressed glucose uptake and glycolytic flux leading to starvation and the induction of caspase-independent cell death associated with autophagy. Alternate carbon sources reduced cell death and autophagy induction after NF?B inhibition, underlining the impact of starvation on cell death. In contrast, inhibitors of autophagy and oxidative phosphorylation specifically accelerated cell death after NF?B inhibition. Thus, autophagy and mitochondrial metabolism serve as pro-survival pathways after NF?B inhibition. Small molecule-mediated IKK? inhibition in diffuse large B-cell lymphomas, EBV transformed B-cells and Karposi sarcoma herpesvirus infected primary effusion lymphomas induced starvation, autophagy, and rendered cells more sensitive to inhibitors mitochondrial metabolism. Thus, IKK?i mimics the metabolic phenotype observed in NF?B-inhibited LCLs. 
Taken together, the results of this work suggest that NF?B signaling establishes a metabolic program supporting proliferation and apoptosis resistance by driving glucose import. The combined targeting of NF?B pathway and mitochondrial metabolism might be a valid synthetic lethal approach to treat B-cell malignancies. 

KW  - B-Zell-Lymphom
KW  - Epstein-Barr-Virus
KW  - Aerober Stoffwechsel
KW  - Anaerober Stoffwechsel
KW  - Burkitt-Lymphom
KW  - Glucosestoffwechsel
KW  - Autophagie <Physiologie>
CY  - Erlangen
PB  - Universitätsbibliothek der Universität Erlangen-Nürnberg
AD  - Universitätsstraße. 4, 91054 Erlangen
L2  - http://www.opus.ub.uni-erlangen.de/opus/volltexte/2012/3225
ER  -