title: The hexosamine biosynthetic pathway couples growth factor-induced glutamine uptake to glucose metabolism.
abstract: Glucose and glutamine serve as the two primary carbon sources in proliferating cells, and uptake of both nutrients is directed by growth factor signaling. Although either glucose or glutamine can potentially support mitochondrial tricarboxylic acid (TCA) cycle integrity and ATP production, we found that glucose deprivation led to a marked reduction in glutamine uptake and progressive cellular atrophy in multiple mammalian cell types. Despite the continuous presence of growth factor and an abundant supply of extracellular glutamine, interleukin-3 (IL-3)-dependent cells were unable to maintain TCA cycle metabolite pools or receptor-dependent signal transduction when deprived of glucose. This was due at least in part to down-regulation of IL-3 receptor α (IL-3Rα) surface expression in the absence of glucose. Treatment of glucose-starved cells with N-acetylglucosamine (GlcNAc) to maintain hexosamine biosynthesis restored mitochondrial metabolism and cell growth by promoting IL-3-dependent glutamine uptake and metabolism. Thus, glucose metabolism through the hexosamine biosynthetic pathway is required to sustain sufficient growth factor signaling and glutamine uptake to support cell growth and survival.
authors.affiliation: Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Wellen
authors.forename: Chao
authors.initials: C
authors.lastname: Lu
authors.forename: Anthony
authors.initials: A
authors.lastname: Mancuso
authors.forename: Johanna M S
authors.initials: JM
authors.lastname: Lemons
authors.forename: Michael
authors.initials: M
authors.lastname: Ryczko
authors.forename: James W
authors.initials: JW
authors.lastname: Dennis
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: Hilary A
authors.initials: HA
authors.lastname: Coller
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D000117:Acetylglucosamine / Q000494:pharmacology; D000818:Animals; D001284:Atrophy; D001692:Biological Transport; D002470:Cell Survival; D002952:Citric Acid Cycle; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006595:Hexosamines / Q000096:biosynthesis*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007377:Interleukin-3; D053858:Metabolic Networks and Pathways; D051379:Mice; D015398:Signal Transduction
chemical_list: D006595:Hexosamines; D036341:Intercellular Signaling Peptides and Proteins; D007377:Interleukin-3; D005973:Glutamine; D005947:Glucose; D000117:Acetylglucosamine