Abstract
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 G2–M fraction. The DATS-induced cell cycle arrest in PC-3 cells was associated with increased Tyr15 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 Ser216 phosphorylation. The DATS-mediated decrease in protein level and Ser216 phosphorylation of Cdc25C as well as G2–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 G2–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 G2–M phase cell cycle arrest in human prostate cancer cells is caused by ROS-mediated destruction and hyperphosphorylation of Cdc25C.
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Acknowledgements
This study was supported in part by United States Public Health Service Grants RO1 CA113363-01, RO1 CA101753-02 and RO1 CA076348-07 (to SVS) awarded by the National Cancer Institute, and a Developmental Research Grant from the UPCI Lung Cancer SPORE. We thank Karen Lew and Yan Zeng for technical assistance.
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Xiao, D., Herman-Antosiewicz, A., Antosiewicz, J. et al. 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. Oncogene 24, 6256–6268 (2005). https://doi.org/10.1038/sj.onc.1208759
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DOI: https://doi.org/10.1038/sj.onc.1208759
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