Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation

Metin Kurtoglu, Ningguo Gao, Jie Shang, Johnathan C. Maher, Mark A. Lehrman, Medhi Wangpaichitr, Niramol Savaraj, Andrew N. Lane, Theodore Lampidis

Research output: Contribution to journalArticle

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Abstract

In tumor cells growing under hypoxia, inhibiting glycolysis with 2-deoxy-D-glucose (2-DG) leads to cell death, whereas under normoxic conditions cells similarly treated survive. Surprisingly, here we find that 2-DG is toxic in select tumor cell lines growing under normal oxygen tension. In contrast, a more potent glycolytic inhibitor, 2-fluorodeoxy-D-glucose, shows little or no toxicity in these cell types, indicating that a mechanism other than inhibition of glycolysis is responsible for their sensitivity to 2-DG under normoxia. A clue to this other mechanism comes from previous studies in which it was shown that 2-DG interferes with viral N-linked glycosylation and is reversible by exogenous addition of mannose. Similarly, we find that 2-DG interferes with N-linked glycosylation more potently in the tumor cell types that are sensitive to 2-DG under normoxia, which can be reversed by exogenous mannose. Additionally, 2-DG induces an unfolded protein response, including up-regulation of GADD153 (C/EBP-homologous protein), an unfolded protein response-specific mediator of apoptosis, more effectively in 2-DG-sensitive cells. We conclude that 2-DG seems to be toxic in select tumor cell types growing under normoxia by inhibition of N-linked glycosylation and not by glycolysis. Because in a phase I study 2-DG is used in combination with an anticancer agent to target hypoxic cells, our results raise the possibility that in certain cases, 2-DG could be used as a single agent to selectively kill both the aerobic (via interference with glycosylation) and hypoxic (via inhibition of glycolysis) cells of a solid tumor.

Original languageEnglish
Pages (from-to)3049-3058
Number of pages10
JournalMolecular Cancer Therapeutics
Volume6
Issue number11
DOIs
StatePublished - Nov 1 2007

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Deoxyglucose
Glycolysis
Glycosylation
Cell Death
Neoplasms
Unfolded Protein Response
Poisons
Mannose
Transcription Factor CHOP
Protein Unfolding
Tumor Cell Line
Antineoplastic Agents
Up-Regulation
Apoptosis
Oxygen
Glucose

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation. / Kurtoglu, Metin; Gao, Ningguo; Shang, Jie; Maher, Johnathan C.; Lehrman, Mark A.; Wangpaichitr, Medhi; Savaraj, Niramol; Lane, Andrew N.; Lampidis, Theodore.

In: Molecular Cancer Therapeutics, Vol. 6, No. 11, 01.11.2007, p. 3049-3058.

Research output: Contribution to journalArticle

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abstract = "In tumor cells growing under hypoxia, inhibiting glycolysis with 2-deoxy-D-glucose (2-DG) leads to cell death, whereas under normoxic conditions cells similarly treated survive. Surprisingly, here we find that 2-DG is toxic in select tumor cell lines growing under normal oxygen tension. In contrast, a more potent glycolytic inhibitor, 2-fluorodeoxy-D-glucose, shows little or no toxicity in these cell types, indicating that a mechanism other than inhibition of glycolysis is responsible for their sensitivity to 2-DG under normoxia. A clue to this other mechanism comes from previous studies in which it was shown that 2-DG interferes with viral N-linked glycosylation and is reversible by exogenous addition of mannose. Similarly, we find that 2-DG interferes with N-linked glycosylation more potently in the tumor cell types that are sensitive to 2-DG under normoxia, which can be reversed by exogenous mannose. Additionally, 2-DG induces an unfolded protein response, including up-regulation of GADD153 (C/EBP-homologous protein), an unfolded protein response-specific mediator of apoptosis, more effectively in 2-DG-sensitive cells. We conclude that 2-DG seems to be toxic in select tumor cell types growing under normoxia by inhibition of N-linked glycosylation and not by glycolysis. Because in a phase I study 2-DG is used in combination with an anticancer agent to target hypoxic cells, our results raise the possibility that in certain cases, 2-DG could be used as a single agent to selectively kill both the aerobic (via interference with glycosylation) and hypoxic (via inhibition of glycolysis) cells of a solid tumor.",
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