期刊
MOLECULAR CANCER THERAPEUTICS
卷 6, 期 11, 页码 3049-3058出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-07-0310
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- NCI NIH HHS [CA37109] Funding Source: Medline
- NIGMS NIH HHS [R01 GM038545-20, GM38545, R01 GM038545] Funding Source: Medline
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].
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