Cited 32 times in
Compound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1.
|dc.contributor.author||Min, do S||-|
|dc.description.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-FLIP(L) and Mcl-1 contributes to compound C-enhanced TRAIL-induced apoptosis. Reduced expression of c-FLIP(L) and Mcl-1 were caused by the decreased protein stability of c-FLIP(L) 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-FLIP(L) 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-FLIP(L) 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-FLIP(L) and Mcl-1 down-regulation.||-|
|dc.subject.MESH||AMP-Activated Protein Kinases/antagonists & inhibitors/genetics/metabolism||-|
|dc.subject.MESH||CASP8 and FADD-Like Apoptosis Regulating Protein/genetics/*metabolism||-|
|dc.subject.MESH||Cell Proliferation/drug effects||-|
|dc.subject.MESH||Proto-Oncogene Proteins c-bcl-2/genetics/*metabolism||-|
|dc.subject.MESH||RNA, Small Interfering/pharmacology||-|
|dc.subject.MESH||Reactive Oxygen Species/*metabolism||-|
|dc.subject.MESH||Reverse Transcriptase Polymerase Chain Reaction||-|
|dc.subject.MESH||TNF-Related Apoptosis-Inducing Ligand/genetics/*metabolism||-|
|dc.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.||-|
|dc.citation.title||Experimental cell research||-|
|dc.identifier.bibliographicCitation||Experimental cell research, 316(13):2194-2203, 2010||-|
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.