title: Inhibition of Cathepsin S Induces Mitochondrial ROS That Sensitizes TRAIL-Mediated Apoptosis Through p53-Mediated Downregulation of Bcl-2 and c-FLIP.
abstract: Cathepsin S is highly expressed in various cancer cells, and it has protumoral effects, including promotion of migration, invasion, and neovascularization. In this study, we show that inhibition of cathepsin S could sensitize cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis.
  
  
  
  An inhibitor of cathepsin S (Z-FL-COCHO; ZFL) markedly induced apoptosis in human renal cancer cells treated with TRAIL. In contrast, combined treatment with ZFL and TRAIL had no effect on normal cells. ZFL downregulated Bcl-2 expression at the transcriptional level in a p53-dependent manner, and overexpression of Bcl-2 also markedly blocked apoptosis induced by combined treatment with ZFL and TRAIL. In addition, ZFL induced downregulation of c-FLIP, and overexpression of c-FLIP blocked the apoptosis induced by ZFL plus TRAIL. Moreover, ZFL increased the expression of Cbl, an E3 ligase of c-FLIP, in a p53-dependent manner, and knockdown of Cbl markedly prevented c-FLIP downregulation and the apoptosis induced by ZFL plus TRAIL. Interestingly, ZFL induced p53 expression via production of mitochondrial reactive oxygen species (ROS). We also demonstrated that downregulation of cathepsin S by small interfering RNA sensitized TRAIL-mediated apoptosis in Caki cells.
  
  
  
  These results reveal the importance of cathepsin S on resistance against TRAIL, and inhibition of cathepsin S activity plays a crucial role in TRAIL-mediated cell death of cancer cells.
  
  
  
  Our results indicated that inhibition of cathepsin S stimulates TRAIL-induced apoptosis through downregulation of Bcl-2 and Cbl-mediated c-FLIP by ROS-mediated p53 expression. Antioxid. Redox Signal. 27, 215-233.
authors.affiliation: 1 Department of Immunology, School of Medicine, Keimyung University , Daegu, South Korea .
authors.forename: Bo Ram
authors.initials: BR
authors.lastname: Seo
authors.affiliation: 1 Department of Immunology, School of Medicine, Keimyung University , Daegu, South Korea .
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Min
authors.affiliation: 1 Department of Immunology, School of Medicine, Keimyung University , Daegu, South Korea .
authors.forename: Seon Min
authors.initials: SM
authors.lastname: Woo
authors.affiliation: 2 Department of Pathology, School of Medicine, Keimyung University , Daegu, South Korea .
authors.forename: Misun
authors.initials: M
authors.lastname: Choe
authors.affiliation: 3 Department of Biochemistry & Molecular Biology, Ajou University School of Medicine , Suwon, South Korea .
authors.forename: Kyeong Sook
authors.initials: KS
authors.lastname: Choi
authors.affiliation: 3 Department of Biochemistry & Molecular Biology, Ajou University School of Medicine , Suwon, South Korea .
authors.forename: Young-Kyung
authors.initials: YK
authors.lastname: Lee
authors.affiliation: 3 Department of Biochemistry & Molecular Biology, Ajou University School of Medicine , Suwon, South Korea .
authors.forename: Gyesoon
authors.initials: G
authors.lastname: Yoon
authors.affiliation: 1 Department of Immunology, School of Medicine, Keimyung University , Daegu, South Korea .
authors.forename: Taeg Kyu
authors.initials: TK
authors.lastname: Kwon
mesh_terms: D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D053221:TNF-Related Apoptosis-Inducing Ligand; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D002403:Cathepsins; C028217:cathepsin S
keywords: Bcl-2; Cbl; TRAIL; c-FLIP; cathepsin S; p53