Caffeine induces G2/M arrest and apoptosis via a novel p53-dependent pathway in NB4 promyelocytic leukemia cells.
Methylxantine derivative, caffeine, is known to prevent the p53-dependent apoptosis pathway via inhibition of ATM (ataxia telangiectasia mutated) kinase, which activates p53 by phosphorylation of the Ser-15 residue. In contrast, it has been reported that caffeine induces p53-mediated apoptosis through Bax protein in non-small-cell lung cancer cells. Therefore, the effects of caffeine on cellular growth in malignant cells are controversial. We investigated the effects of caffeine on cell proliferation, cell cycle progression, and induction of apoptosis in NB4 promyelocytic leukemia cells containing wild-type p53. Caffeine suppressed the cellular growth of NB4 cells in a dose- and time-dependent manner. Caffeine induced G(2)/M phase cell cycle arrest in NB4 cells in association with the induction of phosphorylation at the Ser-15 residue of p53 and induction of tyrosine phosphorylation of cdc2. Expression of Bax protein was increased in NB4 cells after treatment with caffeine. Interestingly, the antisense oligonucleotides for p53 significantly reduced p53 expression and caffeine-induced G(2)/M phase cell cycle arrest in NB4 cells. These results suggest that caffeine induces cell cycle arrest and apoptosis in association with activation of p53 by a novel pathway to phosphorylate the Ser-15 residue and induction of phosphorylation of cdc 2 in leukemic cells with normal p53.
Ito
Keisuke
K
Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
Nakazato
Tomonori
T
Miyakawa
Yoshitaka
Y
Yamato
Kenji
K
Ikeda
Yasuo
Y
Kizaki
Masahiro
M
D017209:Apoptosis / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000473:pathology* / Q000503:physiopathology*; D008928:Mitochondria / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D016376:Oligonucleotides, Antisense; D016159:Tumor Suppressor Protein p53; D002110:Caffeine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases