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 J. Lampidis, Jaime R. Merchan

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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