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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.

DC Field Value Language
dc.contributor.authorJang, JH-
dc.contributor.authorLee, TJ-
dc.contributor.authorYang, ES-
dc.contributor.authorMin, do S-
dc.contributor.authorKim, YH-
dc.contributor.authorKim, SH-
dc.contributor.authorChoi, YH-
dc.contributor.authorPark, JW-
dc.contributor.authorChoi, KS-
dc.contributor.authorKwon, TK-
dc.date.accessioned2011-05-31T02:06:51Z-
dc.date.available2011-05-31T02:06:51Z-
dc.date.issued2010-
dc.identifier.issn0014-4827-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/2734-
dc.description.abstractThe 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.language.isoen-
dc.subject.MESHAMP-Activated Protein Kinases/antagonists & inhibitors/genetics/metabolism-
dc.subject.MESHApoptosis/*drug effects-
dc.subject.MESHBlotting, Western-
dc.subject.MESHCASP8 and FADD-Like Apoptosis Regulating Protein/genetics/*metabolism-
dc.subject.MESHCell Proliferation/drug effects-
dc.subject.MESHCells, Cultured-
dc.subject.MESHFibroblasts/metabolism/pathology-
dc.subject.MESHFlow Cytometry-
dc.subject.MESHHumans-
dc.subject.MESHKidney Neoplasms/metabolism/*pathology-
dc.subject.MESHMesangial Cells/metabolism/pathology-
dc.subject.MESHProto-Oncogene Proteins c-bcl-2/genetics/*metabolism-
dc.subject.MESHPyrazoles/*pharmacology-
dc.subject.MESHPyrimidines/*pharmacology-
dc.subject.MESHRNA, Messenger/genetics-
dc.subject.MESHRNA, Small Interfering/pharmacology-
dc.subject.MESHReactive Oxygen Species/*metabolism-
dc.subject.MESHReverse Transcriptase Polymerase Chain Reaction-
dc.subject.MESHTNF-Related Apoptosis-Inducing Ligand/genetics/*metabolism-
dc.titleCompound C sensitizes Caki renal cancer cells to TRAIL-induced apoptosis through reactive oxygen species-mediated down-regulation of c-FLIPL and Mcl-1.-
dc.typeArticle-
dc.identifier.pmid20451517-
dc.identifier.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0014-4827(10)00199-0-
dc.contributor.affiliatedAuthor최, 경숙-
dc.type.localJournal Papers-
dc.identifier.doi10.1016/j.yexcr.2010.04.028-
dc.citation.titleExperimental cell research-
dc.citation.volume316-
dc.citation.number13-
dc.citation.date2010-
dc.citation.startPage2194-
dc.citation.endPage2203-
dc.identifier.bibliographicCitationExperimental cell research, 316(13):2194-2203, 2010-
dc.identifier.eissn1090-2422-
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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