Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1

Title
Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1
Author(s)
이태진권택규[권택규]장지훈[장지훈]김영호[김영호]양은선[양은선]민도식[민도식]김상현[김상현]최영현[최영현]최경숙[최경숙]박종욱[박종욱]
Keywords
ACTIVATED PROTEIN-KINASE; OXIDATIVE STRESS; PATHWAY; DEATH; DEGRADATION; INHIBITION; DEFICIENCY; PROTEASOME; EXPRESSION; PREVENTS
Issue Date
201005
Publisher
ELSEVIER INC
Citation
EXPERIMENTAL CELL RESEARCH, v.316, no.13, pp.2194 - 2203
Abstract
The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), either alone or in combination with other anticancer drugs, is considered as a new strategy for anticancer therapy. Compound C, a cell-permeable pyrrazolopyrimidine derivative, acts as a potent, selective, reversible ATP-competitive inhibitor of AMP-activated protein kinase (AMPK). In this study, we show that compound C sensitizes Caki human renal cancer cells, but not normal human skin fibroblast cells (HSF) and human mesangial cells, to TRAIL-mediated apoptosis. However, AMPK siRNA failed to affect TRAIL-mediated apoptosis in Caki cells and transduction of dominant negative AMPK rather attenuated TRAIL-induced apoptosis, indicating that the effect of compound C on sensitization of TRAIL-induced apoptosis is independent of AMPK activity. Interestingly, we found that down-regulation of c-FLIPL and Mcl-1 contributes to compound C-enhanced TRAIL-induced apoptosis. Reduced expression of c-FLIPL and Mcl-1 were caused by the decreased protein stability of c-FLIPL and Mcl-1, but not by their transcriptional control, in compound C-treated cells. Pretreatment with N-acetyl-L-cysteine (NAC) significantly inhibited the cell death induced by the combined treatment with compound C and TRAIL as well as recovered the expression levels of c-FLIPL and Mcl-1 down-regulated by the combinatory treatment with compound C plus TRAIL, suggesting that compound C-stimulated TRAIL-induced apoptosis appears to be dependent on the generation of reactive oxygen species for down-regulation of c-FLIPL and Mcl-1. Taken together, the present study demonstrates that compound C enhances TRAIL-induced apoptosis in human renal cancer cells by ROS-mediated c-FLIPL and Mcl-1 down-regulation. (C) 2010 Elsevier Inc. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/22469http://dx.doi.org/10.1016/j.yexcr.2010.04.028
ISSN
0014-4827
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의과대학 > 해부학교실 > Articles
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