Year: 2012
Type: dissertation
Abstract: 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 NFκB pathway controls glucose import via GLUT1 membrane trafficking in both viral and spontaneous B-cell lymphomas. To promote GLUT1 translocation the NFκB pathway activates the signaling cascade from PI3K to GLUT1 plasma membrane translocation at two distinct points. First, the NFκB-stimulating IκB-kinase β (IKKβ) supported Phosphatidylinositol-3-kinase (PI3K) driven AKT activity. Second, NFκB-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 NFκB 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 NFκB. In Epstein Barr virus (EBV) transformed B-cells the NFκB pathway was essential to sustain energy homeostasis and survival. Inhibition of NFκB-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 NFκB inhibition, underlining the impact of starvation on cell death. In contrast, inhibitors of autophagy and oxidative phosphorylation specifically accelerated cell death after NFκB inhibition. Thus, autophagy and mitochondrial metabolism serve as pro-survival pathways after NFκB inhibition. Small molecule-mediated IKKβ 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, IKKβi mimics the metabolic phenotype observed in NFκB-inhibited LCLs. Taken together, the results of this work suggest that NFκB signaling establishes a metabolic program supporting proliferation and apoptosis resistance by driving glucose import. The combined targeting of NFκB pathway and mitochondrial metabolism might be a valid synthetic lethal approach to treat B-cell malignancies.
Author: Thomas Sommermann
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3155738407