Caffeine induces TP53-independent G(1)-phase arrest and apoptosis in human lung tumor cells in a dose-dependent manner

Radiat Res. 2002 Feb;157(2):166-74. doi: 10.1667/0033-7587(2002)157[0166:citigp]2.0.co;2.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology*
  • Apoptosis / drug effects*
  • CDC2 Protein Kinase / antagonists & inhibitors
  • CDC2 Protein Kinase / physiology
  • CDC2-CDC28 Kinases*
  • Caffeine / administration & dosage
  • Caffeine / pharmacology*
  • Cell Cycle Proteins / physiology
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / physiology
  • Cyclins / analysis
  • Cyclins / physiology
  • Dose-Response Relationship, Drug
  • G1 Phase / drug effects*
  • G2 Phase / drug effects
  • G2 Phase / radiation effects
  • Gamma Rays / adverse effects
  • Genes, p53
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology*
  • Microtubules / drug effects
  • Neoplasm Proteins / analysis
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology
  • Nocodazole / pharmacology
  • Protein Kinases / analysis
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / physiology
  • Radiation-Sensitizing Agents / administration & dosage
  • Radiation-Sensitizing Agents / pharmacology*
  • Tumor Suppressor Protein p53 / analysis
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / physiology*
  • cdc25 Phosphatases / physiology

Substances

  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • Neoplasm Proteins
  • Radiation-Sensitizing Agents
  • Tumor Suppressor Protein p53
  • Caffeine
  • Protein Kinases
  • histone H1 kinase
  • Protein Serine-Threonine Kinases
  • CDC2 Protein Kinase
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • CDC25C protein, human
  • cdc25 Phosphatases
  • Nocodazole