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Research Articles: Therapeutics, Targets, and Development

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

¹ Department of Cell Biology and Anatomy and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine; ² VA Medical Hospital, Miami, Florida; ³ Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas; and ⁴ James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky

Requests for reprints: Theodore J. Lampidis, PAP Building, Room 115, 1550 Northwest 10th Avenue, Miami, FL 33136. Phone: 305-243-4846; Fax: 305-243-3414. E-mail: tlampidi{at}med.miami.edu

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. [Mol Cancer Ther 2007;6(11):3049–58]

Grant support: National Cancer Institute grant CA37109, State of Florida, Bankhead Coley BCBG1-10, Sylvester Comprehensive Cancer Center, and funds from Threshold Pharmaceuticals Inc. (T.J. Lampidis); NIH GM38545 and Welch Foundation I-1168 (M.A. Lehrman).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 5/ 3/07; revised 7/20/07; accepted 9/20/07.