Vitamin C transiently arrests cancer cell cycle progression in S phase and G2/M boundary by modulating the kinetics of activation and the subcellular localization of Cdc25C phosphatase.
Regulation of cell cycle progression involves redox (oxidation-reduction)-dependent modification of proteins including the mitosis-inducing phosphatase Cdc25C. The role of vitamin C (ascorbic acid, ASC), a known modulator of the cellular redox status, in regulating mitotic entry was investigated in this study. We demonstrated that vitamin C inhibits DNA synthesis in HeLa cells and, mainly the form of dehydroascorbic acid (DHA), delays the entry of p53-deficient synchronized HeLa and T98G cancer cells into mitosis. High concentrations of Vitamin C caused transient S and G2 arrest in both cell lines by delaying the activation of the M-phase promoting factor (MPF), Cdc2/cyclin-B complex. Although vitamin C did not inhibit the accumulation of cyclin-B1, it may have increased the level of Cdc2 inhibitory phosphorylation. This was achieved by transiently maintaining Cdc25C, the activator of Cdc2, both in low levels and in a phosphorylated on Ser216 inactive form that binds to 14-3-3 proteins contributing thus to the nuclear exclusion of Cdc25C. As expected, vitamin C prevented the nuclear accumulation of Cdc25C in both cell lines. In conclusion, it seems that vitamin C induces transient cell cycle arrest, at least in part, by delaying the accumulation and the activation of Cdc25C.
Thomas
Christopher G
CG
Laboratory of Physiology, Unit of Cellular and Molecular Physiology, Faculty of Medicine, University of Ioannina, Ioannina, Greece.
Vezyraki
Patra E
PE
Kalfakakou
Vicky P
VP
Evangelou
Angelos M
AM
D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008938:Mitosis / Q000187:drug effects*; D008954:Models, Biological; D016196:S Phase / Q000187:drug effects*; D020687:cdc25 Phosphatases / Q000378:metabolism*
D000975:Antioxidants; D018797:Cell Cycle Proteins; D004247:DNA; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D001205:Ascorbic Acid