title: 2-Deoxy-Glucose Downregulates Endothelial AKT and ERK via Interference with N-Linked Glycosylation, Induction of Endoplasmic Reticulum Stress, and GSK3β Activation.
abstract: Interference with endothelial cell metabolism is a promising, yet unexploited strategy for angiogenesis inhibition. We reported that the glucose analogue 2-deoxy-D-glucose (2-DG) inhibits angiogenesis at significantly lower concentrations than those required for tumor cytotoxicity. Here, we found that hypersensitivity to 2-DG in endothelial cells is not associated with enhanced drug uptake compared with tumor cells, but with time-dependent, endothelial-selective inhibition of AKT and ERK phosphorylation. Downregulation of these critical survival pathways is shown to be due to 2-DG's interference with N-linked glycosylation, leading to alterations in VEGFR2 (and downstream signaling) as well as induction of endoplasmic reticulum (ER) stress, GSK3β activation, and apoptosis. In vivo, periocular administration of 2-DG in LHBETATAG mice was associated with significant reduction of newly formed (CD105(+)) tumor capillaries, ER stress (GRP 78 expression), and endothelial apoptosis (TUNEL). These findings uniquely link N-linked glycosylation inhibition, ER stress, and ERK/AKT downregulation in endothelial cells, and provide a novel drug development strategy to overcome resistance mechanisms to currently available antiangiogenic agents.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Kovács
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Christina
authors.initials: C
authors.lastname: Decatur
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Marcela
authors.initials: M
authors.lastname: Toro
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Dien G
authors.initials: DG
authors.lastname: Pham
authors.affiliation: Department of Cell Biology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Huaping
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Jing
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Murray
authors.affiliation: Department of Cell Biology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Lampidis
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida. jmerchan2@med.miami.edu.
authors.forename: Jaime R
authors.initials: JR
authors.lastname: Merchan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000008:administration & dosage* / Q000494:pharmacology; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006031:Glycosylation / Q000187:drug effects; D019073:HT29 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D003847:Deoxyglucose; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3