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Induction of Apoptosis by Caffeine Is Mediated by the p53, Bax, and Caspase 3 Pathways¹

Hormel Institute, University of Minnesota, Austin, Minnesota 55912 [Z. H., W-Y. M., T. H., A. M. B., Z. D.], and Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854 [C. S. Y.]

Caffeine is a key component of many popular drinks, especially tea and coffee. Previous reports have shown that caffeine may contribute to the chemopreventive effect of tea in animals. Here, we report that treatment with low concentrations of caffeine induced apoptosis in JB6 Cl41 cells. JB6 Cl41 cells were starved in 0.1% fetal bovine serum/MEM for 72 h and then treated with 50–450 µM caffeine for 24 h. Cells showed the typical DNA laddering pattern and other characteristics of apoptosis. The IC₅₀ of caffeine on JB6 Cl41 cells was 2.7 mM. Induction of apoptosis by caffeine appeared to be p53-dependent because cells lacking p53 (p53^-/-) showed no signs of apoptosis after treatment with caffeine. Immunoprecipitation assays and Western blot analysis showed that caffeine induced phosphorylation of p53 at Ser¹⁵ in JB6 Cl41 cells. The same low concentration of caffeine that was effective for inducing phosphorylation of p53 was also shown to increase p53 activation. Expression of Bax, another p53 target, distinctly increased in a time- and dose-dependent manner. Cleaved caspase 3 was also increased in a time- and dose-dependent manner. These data show that a low concentration of caffeine can induce p53-dependent apoptosis in JB6 cells through the Bax and caspase 3 pathways.

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