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

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

Author information

1
Department of Medicine, Division of Hematology-Oncology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
2
Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
3
Department of Cell Biology, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, Florida.
4
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.

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.

PMID:
26637370
PMCID:
PMC4747846
DOI:
10.1158/1535-7163.MCT-14-0315
[Indexed for MEDLINE]
Free PMC Article

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