Abstract
YM155, a small-molecule survivin inhibitor, has been reported for its anti-cancer activity in various cancer cells. In this study, we investigated the effect of YM155 to enhance TRAIL-mediated apoptosis in human renal carcinoma cells. We found that YM155 alone had no effect on apoptosis, however, combined treatment with YM155 and TRAIL markedly induced apoptosis in human renal carcinoma cells (Caki, ACHN, and A498), breast cancer cells (MDA-MB231), and glioma cells (U251MG), but not normal cells [mesangial cell (MC) and human skin fibroblast (HSF)]. YM155 induced down-regulation of Mcl-1 expression at the post-translational levels, and the overexpression of Mcl-1 markedly inhibited YM155 plus TRAIL-induced apoptosis. Furthermore, YM155 induced down-regulation of c-FLIP mRNA expression through inhibition of NF-κB transcriptional activity. Ectopic expression of c-FLIP markedly blocked YM155-induced TRAIL sensitization. Taken together, our results suggested that YM155 sensitizes TRAIL-mediated apoptosis via down-regulation of Mcl-1 and c-FLIP expression in renal carcinoma Caki cells.
Highlights
Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) selectively induces apoptotic cell death in cancer cells but has no effect on normal cells, it has obtained interest as a promising agent for cancer therapy [1]
Because YM155 has anti-cancer effect on various types of cancer cell [21, 27, 28], we investigated whether YM155 could sensitize TRAIL-mediated apoptosis in human renal carcinoma Caki cells
To confirm whether the YM155 plus TRAILmediated apoptosis is involved in activation of caspase, we examined the effect of pretreatment with z-VAD-fmk, a pan-caspase inhibitor
Summary
Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) selectively induces apoptotic cell death in cancer cells but has no effect on normal cells, it has obtained interest as a promising agent for cancer therapy [1]. TRAIL induced apoptosis begins at the point when it interacts to death receptor (DR) 4 and DR5, and forms death-inducing signal complex (DISC) with recruitment of FAS-associated protein with death domain (FADD) and caspase-8. Activation of caspase-8 by DISC activates caspase-3, and induces apoptosis [2]. Many tumor cells have resistance to TRAILmediated apoptosis [3]. The underlying mechanisms of TRAIL resistance are associated with down-regulation of DR expression, up-regulation of anti-apoptotic proteins expression, such as c-FLIP, anti-apoptotic Bcl-2 family (Bcl-2, Bcl-xL and Mcl-1), inhibitor of apoptosis proteins (IAPs), and down-regulation of pro-apoptotic Bcl-2 family proteins (Bax, Bim and PUMA) [4,5,6,7,8]. The combined treatment with the TRAIL sensitizers is required to overcome TRAIL resistance
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