Diallyl trisulfide-induced G(2)-M phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species-dependent destruction and hyperphosphorylation of Cdc 25 C.
Molecular mechanism of cell cycle arrest caused by diallyl trisulfide (DATS), a garlic-derived cancer chemopreventive agent, has been investigated using PC-3 and DU 145 human prostate cancer cells as a model. Treatment of PC-3 and DU 145 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 (Cdk 1) and inhibition of Cdk 1/cyclinB 1 kinase activity. The DATS-treated PC-3 and DU 145 cells also exhibited a decrease in the protein level of Cdc 25 C and an increase in its Ser(216) phosphorylation. The DATS-mediated decrease in protein level and Ser(216) phosphorylation of Cdc 25 C 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 DU 145 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 Cdc 25 C.
Xiao
Dong
D
Department of Pharmacology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Herman-Antosiewicz
Anna
A
Antosiewicz
Jedrzej
J
Xiao
Hui
H
Brisson
Marni
M
Lazo
John S
JS
Singh
Shivendra V
SV
D000498:Allyl Compounds / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*; D020687:cdc25 Phosphatases / Q000737:chemistry / Q000378:metabolism*
D000498:Allyl Compounds; D018797:Cell Cycle Proteins; D017382:Reactive Oxygen Species; D013440:Sulfides; C042577:diallyl trisulfide; D012694:Serine; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases