2-Deoxy-Glucose Downregulates Endothelial AKT and ERK via Interference with N-Linked Glycosylation, Induction of Endoplasmic Reticulum Stress, and GSK3β Activation

Mol Cancer Ther. 2016 Feb;15(2):264-75. doi: 10.1158/1535-7163.MCT-14-0315. Epub 2015 Dec 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage*
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Deoxyglucose / administration & dosage*
  • Deoxyglucose / pharmacology
  • Down-Regulation
  • Endoplasmic Reticulum Stress / drug effects*
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • Glycosylation / drug effects
  • HT29 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Mice
  • Proto-Oncogene Proteins c-akt / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Angiogenesis Inhibitors
  • Deoxyglucose
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3