Abstract
Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. We demonstrated that the dynamic posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAcylation) is a key metabolic regulator of glucose metabolism. O-GlcNAcylation was induced at serine 529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibited PFK1 activity and redirected glucose flux through the pentose phosphate pathway, thereby conferring a selective growth advantage on cancer cells. Blocking glycosylation of PFK1 at serine 529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal a previously uncharacterized mechanism for the regulation of metabolic pathways in cancer and a possible target for therapeutic intervention.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetylglucosamine / metabolism
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Acylation
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Adenosine Triphosphate / metabolism
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Animals
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Cell Hypoxia
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Cell Line
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Cell Line, Tumor
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Cell Proliferation*
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Glucose / metabolism*
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Glycolysis
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Glycosylation
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Humans
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Lactic Acid / metabolism
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Mice
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Mice, Nude
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N-Acetylglucosaminyltransferases / genetics
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N-Acetylglucosaminyltransferases / metabolism
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NADP / metabolism
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Neoplasms / metabolism*
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Neoplasms / pathology*
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Pentose Phosphate Pathway
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Phosphofructokinase-1, Liver Type / antagonists & inhibitors
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Phosphofructokinase-1, Liver Type / chemistry
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Phosphofructokinase-1, Liver Type / metabolism*
Substances
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Lactic Acid
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NADP
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Adenosine Triphosphate
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N-Acetylglucosaminyltransferases
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O-GlcNAc transferase
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Phosphofructokinase-1, Liver Type
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Glucose
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Acetylglucosamine