Effect of caffeine on the ATR/Chk1 pathway in the epidermis of UVB-irradiated mice

Cancer Res. 2008 Apr 1;68(7):2523-9. doi: 10.1158/0008-5472.CAN-07-5955.

Abstract

Administration of caffeine was shown in earlier studies to enhance UVB-induced apoptosis and inhibit UVB-induced carcinogenesis in hairless SKH-1 mice. Here, we describe a potential mechanism for these in vivo effects. A single irradiation of mouse skin with UVB activated the ataxia-telangiectasia mutated- and Rad3-related (ATR) pathway, causing a severalfold increase in keratinocytes with phospho-Chk1 (Ser(345)) and a marked decrease in mitotic keratinocytes with cyclin B1 compared with baseline. When given in the drinking water for 1 to 2 weeks before UVB, caffeine (0.4 mg/mL) markedly inhibited the UVB-induced phosphorylation of Chk1 on Ser(345) and caused premature expression of cyclin B1 in the epidermis. Normal keratinocytes had delayed mitotic entry for >10 h following UVB. Caffeine administration reduced this mitotic delay to only 4 h and caused markedly increased apoptosis by 6 to 10 h after UVB. p53 knockout mice were used to determine the role of p53 in these processes. Irradiation with UVB markedly decreased the number of mitotic keratinocytes with cyclin B1 in p53 knockout mice, and topical caffeine immediately after UVB abrogated this response and increased UVB-induced apoptosis severalfold. These effects of caffeine in knockout mice were substantially greater than in wild-type mice. The ability of caffeine to promote the deletion of p53(-/-) keratinocytes may be relevant to its inhibitory effect on UVB-induced skin cancer. Our studies indicate that administration of caffeine enhances the removal of DNA-damaged cells by inhibiting the ATR-mediated phosphorylation of Chk1 and prematurely increasing the number of cyclin B1-containing cells that undergo lethal mitosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Ataxia Telangiectasia Mutated Proteins
  • Caffeine / pharmacology*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / metabolism*
  • Checkpoint Kinase 1
  • Cyclin B / metabolism
  • Cyclin B1
  • Female
  • Mice
  • Mice, Hairless
  • Mice, Knockout
  • Mitosis / drug effects
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Skin / cytology
  • Skin / drug effects*
  • Skin / enzymology
  • Skin / radiation effects*
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / etiology
  • Skin Neoplasms / pathology
  • Skin Neoplasms / prevention & control*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Ultraviolet Rays

Substances

  • Ccnb1 protein, mouse
  • Cell Cycle Proteins
  • Cyclin B
  • Cyclin B1
  • Tumor Suppressor Protein p53
  • Caffeine
  • Protein Kinases
  • Atr protein, mouse
  • Ataxia Telangiectasia Mutated Proteins
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Protein-Serine-Threonine Kinases