Chapter 97 - Caffeine, Cyclin D1 and Cell Proliferation

Abstract

Although well characterized as an inhibitor of DNA damage-induced checkpoint signaling, caffeine has also been reported to delay G1-S-phase cell cycle progression in various cell lines. This activity is known to result from the inhibitory effect of caffeine on cyclin-dependent kinase 4/6 activity and occurs independently of p53. Ataxia telangiectasia mutated, a proposed target of caffeine, is required for insulin-induced protein kinase B/Akt phosphorylation and thus indirectly enhances cyclin-dependent kinase 4/6 activity by promoting cyclin D1 synthesis and stability. Caffeine and a selective ataxia telangiectasia mutated inhibitor (KU55933) have been shown to suppress Akt phosphorylation following exposure to insulin. Furthermore, both caffeine and KU55933 have been shown to suppress cyclin D1 expression. These studies suggest that caffeine suppresses G1-S-phase progression by indirectly inhibiting cyclin D1 synthesis and cyclin dependent kinase 4/6 activity. The precise in vivo target(s) of caffeine has not, however, been clearly defined.