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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

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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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  1. Dong Xiao and Anna Herman-Antosiewicz: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pharmacology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Dong Xiao, Anna Herman-Antosiewicz, Jedrzej Antosiewicz, Hui Xiao, Marni Brisson, John S Lazo & Shivendra V Singh

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  1. Dong Xiao
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  2. Anna Herman-Antosiewicz
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Correspondence to Shivendra V Singh.

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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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