title: IKKβ promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3.
abstract: Glutamine is an essential nutrient for cancer cell survival and proliferation. Enhanced utilization of glutamine often depletes its local supply, yet how cancer cells adapt to low glutamine conditions is largely unknown. Here, we report that IκB kinase β (IKKβ) is activated upon glutamine deprivation and is required for cell survival independently of NF-κB transcription. We demonstrate that IKKβ directly interacts with and phosphorylates 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase isoform 3 (PFKFB3), a major driver of aerobic glycolysis, at Ser269 upon glutamine deprivation to inhibit its activity, thereby down-regulating aerobic glycolysis when glutamine levels are low. Thus, due to lack of inhibition of PFKFB3, IKKβ-deficient cells exhibit elevated aerobic glycolysis and lactate production, leading to less glucose carbons contributing to tricarboxylic acid (TCA) cycle intermediates and the pentose phosphate pathway, which results in increased glutamine dependence for both TCA cycle intermediates and reactive oxygen species suppression. Therefore, coinhibition of IKKβ and glutamine metabolism results in dramatic synergistic killing of cancer cells both in vitro and in vivo. In all, our results uncover a previously unidentified role of IKKβ in regulating glycolysis, sensing low-glutamine-induced metabolic stress, and promoting cellular adaptation to nutrient availability.
authors: Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA;
authors: Michael A
authors: MA
authors: Reid
authors: Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA;
authors: Xazmin H
authors: XH
authors: Lowman
authors: Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA;
authors: Min
authors: M
authors: Pan
authors: Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA;
authors: Thai Q
authors: TQ
authors: Tran
authors: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA;
authors: Marc O
authors: MO
authors: Warmoes
authors: Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA;
authors: Mari B
authors: MB
authors: Ishak Gabra
authors: Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA;
authors: Ying
authors: Y
authors: Yang
authors: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27708, USA.
authors: Jason W
authors: JW
authors: Locasale
authors: Department of Cancer Biology, Beckman Research Institute of City of Hope Cancer Center, Duarte, California 91010, USA;
authors: Mei
authors: M
authors: Kong
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D025481:Phosphofructokinase-2 / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D005973:Glutamine; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D051550:I-kappa B Kinase
keywords: IKKβ; PFKFB3; aerobic glycolysis; glutamine; metabolic stress