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Inhibition of Cathepsin S Induces Mitochondrial ROS That Sensitizes TRAIL-Mediated Apoptosis Through p53-Mediated Downregulation of Bcl-2 and c-FLIP

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dc.contributor.authorSeo, BR-
dc.contributor.authorMin, KJ-
dc.contributor.authorWoo, SM-
dc.contributor.authorChoe, M-
dc.contributor.authorChoi, KS-
dc.contributor.authorLee, YK-
dc.contributor.authorYoon, G-
dc.contributor.authorKwon, TK-
dc.date.accessioned2018-08-24T01:49:12Z-
dc.date.available2018-08-24T01:49:12Z-
dc.date.issued2017-
dc.identifier.issn1523-0864-
dc.identifier.urihttp://repository.ajou.ac.kr/handle/201003/15956-
dc.description.abstractAIMS: 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.
RESULTS: 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.
INNOVATION: 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.
CONCLUSION: 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.
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dc.language.isoen-
dc.subject.MESHAnimals-
dc.subject.MESHApoptosis-
dc.subject.MESHCASP8 and FADD-Like Apoptosis Regulating Protein-
dc.subject.MESHCarcinoma, Renal Cell-
dc.subject.MESHCathepsins-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHCell Survival-
dc.subject.MESHDown-Regulation-
dc.subject.MESHDrug Synergism-
dc.subject.MESHEnzyme Inhibitors-
dc.subject.MESHGene Expression Regulation, Neoplastic-
dc.subject.MESHHCT116 Cells-
dc.subject.MESHHumans-
dc.subject.MESHKidney Neoplasms-
dc.subject.MESHMice-
dc.subject.MESHProto-Oncogene Proteins c-bcl-2-
dc.subject.MESHReactive Oxygen Species-
dc.subject.MESHTNF-Related Apoptosis-Inducing Ligand-
dc.subject.MESHTumor Suppressor Protein p53-
dc.subject.MESHXenograft Model Antitumor Assays-
dc.titleInhibition of Cathepsin S Induces Mitochondrial ROS That Sensitizes TRAIL-Mediated Apoptosis Through p53-Mediated Downregulation of Bcl-2 and c-FLIP-
dc.typeArticle-
dc.identifier.pmid27927016-
dc.contributor.affiliatedAuthor최, 경숙-
dc.contributor.affiliatedAuthor이, 영경-
dc.contributor.affiliatedAuthor윤, 계순-
dc.type.localJournal Papers-
dc.identifier.doi10.1089/ars.2016.6749-
dc.citation.titleAntioxidants & redox signaling-
dc.citation.volume27-
dc.citation.number4-
dc.citation.date2017-
dc.citation.startPage215-
dc.citation.endPage233-
dc.identifier.bibliographicCitationAntioxidants & redox signaling, 27(4). : 215-233, 2017-
dc.embargo.liftdate9999-12-31-
dc.embargo.terms9999-12-31-
dc.identifier.eissn1557-7716-
dc.relation.journalidJ015230864-
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Journal Papers > Research Organization > Inflamm-aging Translational Research Center
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