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

Authors
Jang, JH; Lee, TJ; Yang, ES; Min, do S; Kim, YH; Kim, SH; Choi, YH; Park, JW; Choi, KS; Kwon, TK
Citation
Experimental cell research, 316(13):2194-2203, 2010
Journal Title
Experimental cell research
ISSN
0014-48271090-2422
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.
MeSH terms
AMP-Activated Protein Kinases/antagonists & inhibitors/genetics/metabolismApoptosis/*drug effectsBlotting, WesternCASP8 and FADD-Like Apoptosis Regulating Protein/genetics/*metabolismCell Proliferation/drug effectsCells, CulturedFibroblasts/metabolism/pathologyFlow CytometryHumansKidney Neoplasms/metabolism/*pathologyMesangial Cells/metabolism/pathologyProto-Oncogene Proteins c-bcl-2/genetics/*metabolismPyrazoles/*pharmacologyPyrimidines/*pharmacologyRNA, Messenger/geneticsRNA, Small Interfering/pharmacologyReactive Oxygen Species/*metabolismReverse Transcriptase Polymerase Chain ReactionTNF-Related Apoptosis-Inducing Ligand/genetics/*metabolism
DOI
10.1016/j.yexcr.2010.04.028
PMID
20451517
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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