2-deoxy-glucose downregulates endothelial AKT and ERK via interference with N-linked glycosylation, induction of endoplasmic reticulum stress, and GSK3β activation

Krisztina Kovacs, Christina Decatur, Marcela Toro, Dien G. Pham, Huaping Liu, Yuqi Jing, Timothy G. Murray, Theodore Lampidis, Jaime R Merchan

Research output: Contribution to journalArticle

13 Citations (Scopus)

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, GSK3fS activation, and apoptosis. In vivo, periocular administration of 2-DG in LHBETATAGmice 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.

Original languageEnglish (US)
Pages (from-to)264-275
Number of pages12
JournalMolecular Cancer Therapeutics
Volume15
Issue number2
DOIs
StatePublished - Feb 1 2016

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Endoplasmic Reticulum Stress
Deoxyglucose
Glycosylation
Down-Regulation
Endothelial Cells
Glucose
Apoptosis
Neoplasms
Critical Pathways
Angiogenesis Inhibitors
In Situ Nick-End Labeling
Pharmaceutical Preparations
Hypersensitivity
Phosphorylation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

2-deoxy-glucose downregulates endothelial AKT and ERK via interference with N-linked glycosylation, induction of endoplasmic reticulum stress, and GSK3β activation. / Kovacs, Krisztina; Decatur, Christina; Toro, Marcela; Pham, Dien G.; Liu, Huaping; Jing, Yuqi; Murray, Timothy G.; Lampidis, Theodore; Merchan, Jaime R.

In: Molecular Cancer Therapeutics, Vol. 15, No. 2, 01.02.2016, p. 264-275.

Research output: Contribution to journalArticle

Kovacs, Krisztina ; Decatur, Christina ; Toro, Marcela ; Pham, Dien G. ; Liu, Huaping ; Jing, Yuqi ; Murray, Timothy G. ; Lampidis, Theodore ; Merchan, Jaime R. / 2-deoxy-glucose downregulates endothelial AKT and ERK via interference with N-linked glycosylation, induction of endoplasmic reticulum stress, and GSK3β activation. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 2. pp. 264-275.
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