Dicoumarol sensitizes renal cell carcinoma Caki cells to TRAIL-induced apoptosis through down-regulation of Bcl-2, Mcl-1 and c-FLIP in a NQO1-independent manner.

Dicoumarol sensitizes renal cell carcinoma Caki cells to TRAIL-induced apoptosis through down-regulation of Bcl-2, Mcl-1 and c-FLIP in a NQO1-independent manner.
Exp Cell Res. 2014 Jan 22;
Authors: Park EJ, Min KJ, Sook Choi K, Kwon TK
Abstract
In the study, we investigated the effect of dicoumarol, an anti-coagulant agent with the inhibitory activity of NAD(P)H quinone oxidoreductase 1 (NQO1), on TRAIL-induced apoptosis in renal cancer cell. Combined treatment with dicoumarol and TRAIL significantly induced apoptosis in various human renal carcinoma cells including Caki, ACHN, and A498, but not in normal human skin fibroblasts (HSF) and mouse kidney cells (TMCK-1). When we elucidated the relevance of NQO1 in dicoumarol plus TRAIL-mediated apoptosis, both ES936 (a NQO1 inhibitor) and knockdown of NQO1 with siRNA had no effect on TRAIL-mediated apoptosis, suggesting that the stimulating effect of dicoumarol on TRAIL-mediated apoptosis is independent of NQO1 activity. We found that dicoumarol transcriptionally down-regulated Bcl-2 expression via inhibition of NF-κB and CREB activity, whereas it down-regulated Mcl-1 and c-FLIP expression at the post-translational level. Overexpression of Bcl-2, Mcl-1, or c-FLIP overcame the dicoumarol plus TRAIL-induced apoptosis, indicating that downregualtion of these anti-apoptotic proteins may critically contribute to the sensitizing effect of dicoumarol on TRAIL-mediated apoptosis.
PMID: 24462458 [P...

Source: Experimental Cell Research - January 22, 2014 Category: Cytology Authors: Park EJ, Min KJ, Sook Choi K, Kwon TK Tags: Exp Cell Res Source Type: research