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 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 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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