Diallyl trisulfide-induced G2-M phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species-dependent destruction and hyperphosphorylation of Cdc25C

Molecular mechanism of cell cycle arrest caused by diallyl trisulfide (DATS), a garlic-derived cancer chemopreventive agent, has been investigated using PC-3 and DU145 human prostate cancer cells as a model. Treatment of PC-3 and DU145 cells, but not a normal prostate epithelial cell line (PrEC), with growth suppressive concentrations of DATS caused enrichment of the G(2)-M fraction. The DATS-induced cell cycle arrest in PC-3 cells was associated with increased Tyr(15) phosphorylation of cyclin-dependent kinase 1 (Cdk1) and inhibition of Cdk1/cyclinB1 kinase activity. The DATS-treated PC-3 and DU145 cells also exhibited a decrease in the protein level of Cdc25C and an increase in its Ser(216) phosphorylation. The DATS-mediated decrease in protein level and Ser216 phosphorylation of Cdc25C as well as G(2)-M phase cell cycle arrest were significantly attenuated in the presence of N-acetylcysteine implicating reactive oxygen species (ROS) in cell cycle arrest caused by DATS. ROS generation was observed in DATS-treated PC-3 and DU145 cells. DATS treatment also caused an increase in the protein level of Cdk inhibitor p21, but DATS-induced G(2)-M phase arrest was not affected by antisense-mediated suppression of p21 protein level. In conclusion, the results of the present study indicate that DATS-induced G(2)-M phase cell cycle arrest in human prostate cancer cells is caused by ROS-mediated destruction and hyperphosphorylation of Cdc25C.