Carcinogenesis Advance Access published online on September 16, 2005
Carcinogenesis, doi:10.1093/carcin/bgi228
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1 Department of Pharmacology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
* To whom correspondence should be addressed. We have shown previously that apoptosis induction by diallyl trisulfide, a constituent of processed garlic, in PC-3 and DU145 human prostate cancer cells is associated with c-Jun N-terminal kinase and extracellular signal-regulated kinase mediated phosphorylation of Bcl-2. However, pharmacological inhibition of these kinases offers only partial protection against the cell death caused by diallyl trisulfide. Here, we demonstrate that diallyl trisulfide inactivates Akt to trigger apoptosis in prostate cancer cells. Treatment of PC-3/DU145 cells with apoptosis inducing concentration of diallyl trisulfide (40 µM) resulted in a rapid decrease in Ser473 and Thr308 phosphorylation of Akt leading to inhibition of its kinase activity. The diallyl trisulfide-mediated inactivation of Akt was associated with down-regulation of insulin-like growth factor receptor 1 protein level and inhibition of its autophosphorylation. Diallyl trisulfide treatment (40 µM) also caused a decrease in Ser155 and Ser136 phosphorylation of BAD, which is a down-stream target of Akt. Phosphorylation sequesters BAD in the cytoplasm due to increased binding with 14-3-3 proteins. The interaction between BAD and 14-3-3
Received June 30, 2005
Revised August 30, 2005
Accepted September 11, 2005
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Diallyl trisulfide, a constituent of processed garlic, inactivates Akt to trigger mitochondrial translocation of BAD and caspase-mediated apoptosis in human prostate cancer cells
Shivendra V. Singh, E-mail: singhs{at}upmc.edu.
Abstract 
was reduced markedly upon a 4-hour treatment with 40 µM diallyl trisulfide in both cell lines. Consistent with these results, diallyl trisulfide treatment (40 µM, 4 hours) promoted mitochondrial translocation of BAD as revealed by immunohistochemistry. Ectopic expression of constitutively active Akt conferred statistically significant protection against diallyl trisulfide-induced apoptosis. The diallyl trisulfide-induced apoptosis in both cell lines was significantly attenuated in the presence of pan caspase inhibitor zVAD-fmk and caspase-9 specific inhibitor zLEHD-fmk. In conclusion, the present study demonstrates that diallyl trisulfide-induced apoptosis in human prostate cancer cells is mediated, at least in part, by inactivation of Akt signaling axis.
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