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

J Cell Physiol. 2005 Nov;205(2):310-8. doi: 10.1002/jcp.20405.

Abstract

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.

MeSH terms

  • Antioxidants / pharmacology
  • Ascorbic Acid / pharmacology*
  • Cell Cycle / drug effects*
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • DNA / antagonists & inhibitors
  • DNA / biosynthesis
  • Enzyme Activation / drug effects
  • G2 Phase / drug effects*
  • HeLa Cells
  • Humans
  • Kinetics
  • Mitosis / drug effects*
  • Models, Biological
  • S Phase / drug effects*
  • cdc25 Phosphatases / metabolism*

Substances

  • Antioxidants
  • Cell Cycle Proteins
  • DNA
  • CDC25C protein, human
  • cdc25 Phosphatases
  • Ascorbic Acid