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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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Author(s)
Bo Ram SeoKyoung-jin MinSeon Min WooMisun ChoeKyeong Sook ChoiYoung-Kyung LeeGyesoon YoonTaeg Kyu Kwon
Keimyung Author(s)
Choe, Mi SunKwon, Taeg Kyu
Department
Dept. of Pathology (병리학)
Dept. of Immunology (면역학)
Journal Title
Antioxidants & Redox Signaling
Issued Date
2017
Volume
27
Issue
4
Keyword
Bcl-2CblTRAILc-FLIPcathepsin Sp53
Abstract
AIMS:

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.
Keimyung Author(s)(Kor)
최미선
권택규
Publisher
School of Medicine (의과대학)
Citation
Bo Ram Seo et al. (2017). Inhibition of Cathepsin S Induces Mitochondrial ROS That Sensitizes TRAIL-Mediated Apoptosis Through p53-Mediated Downregulation of Bcl-2 and c-FLIP. Antioxidants & Redox Signaling, 27(4), 215–233. doi: 10.1089/ars.2016.6749
Type
Article
ISSN
1523-0864
Source
https://www.liebertpub.com/doi/pdf/10.1089/ars.2016.6749
DOI
10.1089/ars.2016.6749
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/41310
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
1. School of Medicine (의과대학) > Dept. of Pathology (병리학)
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