Caffeine induces TP53-independent G(1)-phase arrest and apoptosis in human lung tumor cells in a dose-dependent manner.
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.
Qi
Wenqing
W
Department of Radiation Oncology, The University of Arizona, 1501 N. Campbell Avenue, P.O. Box 245024, Tucson, Arizona 85724, USA.
Qiao
Dianhua
D
Martinez
Jesse D
JD
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000502:physiology; D042846:CDC2-CDC28 Kinases; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D016213:Cyclins / Q000032:analysis / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects*; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D005720:Gamma Rays / Q000009:adverse effects; D016158:Genes, p53; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008870:Microtubules / Q000187:drug effects; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D015739:Nocodazole / Q000494:pharmacology; D011494:Protein Kinases / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000502:physiology
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D002110:Caffeine; D011494:Protein Kinases; C102333:histone H1 kinase; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D015739:Nocodazole