Abstract
Caffeine is a model radiosensitizing agent that is thought to work by abrogating the radiation-induced G(2)-phase checkpoint. In this study, we examined the effect that various concentrations of caffeine had on cell cycle checkpoints and apoptosis in cells of a human lung carcinoma cell line and found that a concentration of 0.5 mM caffeine could abrogate the G(2)-phase arrest normally seen after exposure to ionizing radiation. Surprisingly, at a concentration of 5 mM, caffeine not only induced apoptosis by itself and acted synergistically to enhance radiation-induced apoptosis, but also induced a TP53-independent G(1)-phase arrest. Examination of the molecular mechanisms by which caffeine produced these effects revealed that caffeine had opposing effects on different cyclin-dependent kinases. CDK2 activity was suppressed by caffeine, whereas activity of CDC2 was enhanced by suppressing phosphorylation on Tyr15 and by interfering with 14-3-3 binding to CDC25C. These data indicate that the effect of caffeine on cell cycle checkpoints and apoptosis is dependent on dose and that caffeine acts through differential regulation of cyclin-dependent kinase activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology*
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Apoptosis / drug effects*
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CDC2 Protein Kinase / antagonists & inhibitors
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CDC2 Protein Kinase / physiology
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CDC2-CDC28 Kinases*
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Caffeine / administration & dosage
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Caffeine / pharmacology*
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Cell Cycle Proteins / physiology
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / physiology
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Cyclins / analysis
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Cyclins / physiology
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Dose-Response Relationship, Drug
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G1 Phase / drug effects*
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G2 Phase / drug effects
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G2 Phase / radiation effects
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Gamma Rays / adverse effects
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Genes, p53
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology*
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Microtubules / drug effects
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Neoplasm Proteins / analysis
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / physiology
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Nocodazole / pharmacology
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Protein Kinases / analysis
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / physiology
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Radiation-Sensitizing Agents / administration & dosage
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Radiation-Sensitizing Agents / pharmacology*
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Tumor Suppressor Protein p53 / analysis
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / physiology*
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cdc25 Phosphatases / physiology
Substances
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Neoplasm Proteins
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Radiation-Sensitizing Agents
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Tumor Suppressor Protein p53
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Caffeine
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Protein Kinases
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histone H1 kinase
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Protein Serine-Threonine Kinases
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CDC2 Protein Kinase
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases
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CDC25C protein, human
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cdc25 Phosphatases
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Nocodazole