title: The hexosamine biosynthesis pathway and O-GlcNAcylation maintain insulin-stimulated PI3K-PKB phosphorylation and tumour cell growth after short-term glucose deprivation.
abstract: Glucose provides an essential nutrient source that supports glycolysis and the hexosamine biosynthesis pathway (HBP) to maintain tumour cell growth and survival. Here we investigated if short-term glucose deprivation specifically modulates the phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) cell survival pathway. Insulin-stimulated PKB activation was strongly abrogated in the absence of extracellular glucose as a consequence of the loss of insulin-stimulated PI3K activation and short-term glucose deprivation inhibited subsequent tumour cell growth. Loss of insulin-stimulated PKB signalling and cell growth was rescued by extracellular glucosamine and increased flux through the HBP. Disruption of O-GlcNAc transferase activity, a terminal step in the HBP, implicated O-GlcNAcylation in PKB signalling and cell growth. Glycogenolysis is known to support cell survival during glucose deprivation, and in A549 lung cancer cells its inhibition attenuates PKB activation which is rescued by increased flux through the HBP. Our studies show that rerouting of glycolytic metabolites to the HBP under glucose-restricted conditions maintains PI3K/PKB signalling enabling cell survival and proliferation.
authors.affiliation: Inositide Laboratory, Cancer Research UK Manchester Institute, University of Manchester, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Willem-Jan
authors.initials: WJ
authors.lastname: Keune
authors.forename: Karen E
authors.initials: KE
authors.lastname: Anderson
authors.forename: Len R
authors.initials: LR
authors.lastname: Stephens
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Hawkins
authors.forename: Nullin
authors.initials: N
authors.lastname: Divecha
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D053898:Biosynthetic Pathways; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004734:Energy Metabolism; D004789:Enzyme Activation; D005947:Glucose / Q000172:deficiency*; D006031:Glycosylation; D006595:Hexosamines / Q000096:biosynthesis*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000378:metabolism; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000117:Acetylglucosamine; D005947:Glucose; D006595:Hexosamines; D006861:Hydrogen Peroxide; D007328:Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D058570:TOR Serine-Threonine Kinases
keywords: Signalling; glucose; insulin; oxidative stress; protein kinase B