Carcinogenesis Advance Access originally published online on September 16, 2005
Carcinogenesis 2006 27(3):533-540; doi:10.1093/carcin/bgi228
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Carcinogenesis vol.27 no.3 © Oxford University Press 2005; all rights reserved.
Diallyl trisulfide, a constituent of processed garlic, inactivates Akt to trigger mitochondrial translocation of BAD and caspase-mediated apoptosis in human prostate cancer cells
Department of Pharmacology and University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
* To whom correspondence should be addressed. Tel: +1 412 623 3263; Fax: +1 412 623 7828; Email: singhs{at}upmc.edu
We have shown previously that apoptosis induction by diallyl trisulfide (DATS), 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 DATS. Here, we demonstrate that DATS inactivates Akt to trigger apoptosis in prostate cancer cells. Treatment of PC-3/DU145 cells with apoptosis inducing concentration of DATS (40 µM) resulted in a rapid decrease in Ser473 and Thr308 phosphorylation of Akt leading to inhibition of its kinase activity. The DATS-mediated inactivation of Akt was associated with downregulation of insulin-like growth factor receptor 1 protein level and inhibition of its autophosphorylation. DATS treatment (40 µM) also caused a decrease in Ser155 and Ser136 phosphorylation of BAD (a proapoptotic protein), which is a downstream target of Akt. Phosphorylation sequesters BAD in the cytoplasm owing to increased binding with 14-3-3 proteins. The interaction between BAD and 14-3-3ß was reduced markedly upon a 4 h treatment with 40 µM DATS in both cell lines. Consistent with these results, DATS treatment (40 µM, 4 h) promoted mitochondrial translocation of BAD as revealed by immunocytochemistry. Ectopic expression of constitutively active Akt conferred statistically significant protection against DATS-induced apoptosis. The DATS-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 DATS-induced apoptosis in human prostate cancer cells is mediated, at least in part, by inactivation of Akt signaling axis.
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