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.
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.
Kurtoglu
Metin
M
Department of Cell Biologoy and Anatomy, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Gao
Ningguo
N
Shang
Jie
J
Maher
Johnathan C
JC
Lehrman
Mark A
MA
Wangpaichitr
Medhi
M
Savaraj
Niramol
N
Lane
Andrew N
AN
Lampidis
Theodore J
TJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000332:Aerobiosis / Q000187:drug effects; D000693:Anaerobiosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology; D006019:Glycolysis / Q000187:drug effects*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D008358:Mannose / Q000494:pharmacology; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D009844:Oligosaccharides / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D017510:Protein Folding; D051742:Transcription Factor CHOP / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D009844:Oligosaccharides; D019788:Fluorodeoxyglucose F18; D051742:Transcription Factor CHOP; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D008358:Mannose; D010100:Oxygen