Garlic Constituent Diallyl Trisulfide Suppresses X-linked Inhibitor of Apoptosis Protein in Prostate Cancer Cells in Culture andIn Vivo

Abstract

We have shown previously that garlic constituent diallyl trisulfide (DATS) inhibits growth of cultured and xenografted human prostate cancer cells in association with apoptosis induction, but the mechanism of cell death is not fully understood. The present study systematically investigates the role of inhibitor of apoptosis (IAP) family proteins in the regulation of DATS-induced apoptosis using cultured PC-3 and LNCaP human prostate cancer cells and dorsolateral prostate from control and DATS-treated transgenic adenocarcinoma of mouse prostate (TRAMP) mice. Level of X-linked inhibitor of apoptosis (XIAP) protein was decreased on 8-hour treatment with 20 and 40 μmol/L DATS, but this effect was partially attenuated at the 16-hour time point. DATS-mediated decline in XIAP protein level was partially reversible in the presence of proteasomal inhibitor MG132. In contrast, DATS-treated PC-3 and LNCaP cells exhibited marked induction of survivin and cellular inhibitor of apoptosis protein 1 (cIAP1) proteins. Induction of survivin protein expression resulting from DATS exposure was associated with an increase in its mRNA level. Dorsolateral prostates from DATS-treated TRAMP mice exhibited statistically significant downregulation of XIAP and induction of survivin protein compared with those of control mice. Ectopic expression of XIAP conferred partial but significant protection against DATS-induced apoptosis. On the other hand, DATS-induced apoptosis was only marginally affected by RNA interference of survivin or cIAP1. In conclusion, the present study indicates that the DATS-induced apoptosis in prostate cancer cells is mediated in part by suppression of XIAP protein expression, and that XIAP represents a viable biomarker of DATS response for future clinical investigations.