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: Krisztina Kovács, Christina Decatur, Marcela Toro, Dien G Pham, Huaping Liu, Yuqi Jing, Timothy G Murray, Theodore J Lampidis, Jaime R Merchan
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 2 Pg. 264-75 (Feb 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 26637370 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• 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

Topics

• Angiogenesis Inhibitors (administration & dosage, pharmacology)
• Animals
• Apoptosis
• Cell Line, Tumor
• Deoxyglucose (administration & dosage, pharmacology)
• Down-Regulation
• Endoplasmic Reticulum Stress (drug effects)
• Endothelial Cells (drug effects, 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)