title: Cystatin SN inhibits auranofin-induced cell death by autophagic induction and ROS regulation via glutathione reductase activity in colorectal cancer.
abstract: Cystatin SN (CST1) is a specific inhibitor belonging to the cystatin superfamily that controls the proteolytic activities of cysteine proteases such as cathepsins. Our previous study showed that high CST1 expression enhances tumor metastasis and invasiveness in colorectal cancer. Recently, auranofin (AF), a gold(I)-containing thioredoxin reductase 1 (TrxR1) inhibitor, has been used clinically to treat rheumatoid arthritis. AF is a proteasome-associated deubiquitinase inhibitor and can act as an anti-tumor agent. In this study, we investigated whether CST1 expression induces autophagy and tumor cell survival. We also investigated the therapeutic effects of AF as an anti-tumor agent in colorectal cancer (CRC) cells. We found that CRC cells expressing high levels of CST1 undergo increased autophagy and exhibit chemotherapeutic resistance to AF-induced cell death, while those expressing low levels of CST1 are sensitive to AF. We also observed that knockdown of CST1 in high-CST1 CRC cells using CST1-specific small interfering RNAs attenuated autophagic activation and restored AF-induced cell mortality. Conversely, the overexpression of CST1 increased autophagy and viability in cells expressing low levels of CST1. Interestingly, high expression of CST1 attenuates AF-induced cell death by inhibiting intracellular reactive oxygen species (ROS) generation, as demonstrated by the fact that the blockage of ROS production reversed AF-induced cell death in CRC cells. In addition, upregulation of CST1 expression increased cellular glutathione reductase (GR) activity, reducing the cellular redox state and inducing autophagy in AF-treated CRC cells. These results suggest that high CST1 expression may be involved in autophagic induction and protects from AF-induced cell death by inhibition of ROS generation through the regulation of GR activity.
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Republic of Korea.
authors.forename: Byung Moo
authors.initials: BM
authors.lastname: Oh
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Republic of Korea.
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Hee Jun
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Yun Sun
authors.initials: YS
authors.lastname: Park
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Jong-Tae
authors.initials: JT
authors.lastname: Kim
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Suk Ran
authors.initials: SR
authors.lastname: Yoon
authors.affiliation: Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Sang Chul
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Lim
authors.affiliation: World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang, Republic of Korea.
authors.forename: Bo-Yeon
authors.initials: BY
authors.lastname: Kim
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Yong-Kyung
authors.initials: YK
authors.lastname: Choe
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.|Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, Republic of Korea.
authors.forename: Hee Gu
authors.initials: HG
authors.lastname: Lee
mesh_terms: D001310:Auranofin / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002403:Cathepsins / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005980:Glutathione Reductase / Q000378:metabolism*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D055333:Salivary Cystatins / Q000378:metabolism / Q000494:pharmacology*; D054481:Thioredoxin Reductase 1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C525171:CST1 protein, human; D061988:Proteasome Inhibitors; D017382:Reactive Oxygen Species; D055333:Salivary Cystatins; D001310:Auranofin; D005980:Glutathione Reductase; D054481:Thioredoxin Reductase 1; D002403:Cathepsins; D046988:Proteasome Endopeptidase Complex