Abstract
The compound 2-deoxyglucose (2-DG) enhances chemotherapy/radiotherapy in cell lines and animal models, prompting two phase I clinical trials with this cancer therapeutic. Although its mechanism of action has not been fully elucidated, it is hypothesized that the molecular basis of 2-DG activity is related to glycolysis inhibition. Here, we report that 2-DG induced Akt phosphorylation at Thr(308) and Ser(473) as early as 15 min post-treatment. These phosphorylation events required phosphatidylinositol-3-kinase activity but were not related to LKB1/AMP-activated protein kinase signaling, the inhibition of glycolysis or epidermal growth factor receptor signaling. The 2-DG-mediated Akt phosphorylation also led to the phosphorylation of Akt downstream targets, such as Foxo3a, GSK3beta, and Chk1. Because the functional consequence of Akt activation includes chemotherapy/radiotherapy resistance, our data suggested that the combination of phosphatidylinositol-3-kinase/Akt inhibitory agents in 2-DG-based chemotherapy/radiotherapy may result in enhanced therapeutic efficacy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases
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Adenosine Triphosphate / metabolism
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Antimetabolites / pharmacology*
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Blotting, Western
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Checkpoint Kinase 1
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Deoxyglucose / pharmacology*
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ErbB Receptors / metabolism
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Fluorescent Antibody Technique
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Forkhead Box Protein O3
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Forkhead Transcription Factors / metabolism
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Glycolysis / drug effects*
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Humans
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Luciferases / metabolism
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Multienzyme Complexes / metabolism*
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Neoplasms / drug therapy
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Neoplasms / metabolism*
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Neoplasms / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Small Interfering / pharmacology
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Signal Transduction
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Tumor Cells, Cultured
Substances
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Antimetabolites
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Multienzyme Complexes
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RNA, Small Interfering
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Adenosine Triphosphate
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Deoxyglucose
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Luciferases
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Protein Kinases
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EGFR protein, human
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ErbB Receptors
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CHEK1 protein, human
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Checkpoint Kinase 1
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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STK11 protein, human
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Glycogen Synthase Kinase 3
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AMP-Activated Protein Kinase Kinases
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AMP-Activated Protein Kinases