title: Extracellular cystatin SN and cathepsin B prevent cellular senescence by inhibiting abnormal glycogen accumulation.
abstract: Cystatin SN (CST1), a known inhibitor of cathepsin B (CatB), has important roles in tumor development. Paradoxically, CatB is a member of the cysteine cathepsin family that acts in cellular processes, such as tumor development and invasion. However, the relationship between CST1 and CatB, and their roles in tumor development are poorly understood. In this study, we observed that the knockdown of CST1 induced the activity of senescence-associated β-galactosidase, a marker of cellular senescence, and expression of senescence-associated secretory phenotype genes, including interleukin-6 and chemokine (C-C motif) ligand 20, in MDA-MB-231 and SW480 cancer cells. Furthermore, CST1 knockdown decreased extracellular CatB activity, and direct CatB inhibition, using specific inhibitors or shCatB, induced cellular senescence. Reconstitution of CST1 restored CatB activity and inhibited cellular senescence in CST1 knockdown cells. CST1 knockdown or CatB inhibition increased glycogen synthase (GS) kinase 3β phosphorylation at serine 9, resulting in the activation of GS and the induction of glycogen accumulation associated with cellular senescence. Importantly, CST1 knockdown suppressed cancer cell proliferation, soft agar colony growth and tumor growth in a xenograft model. These results indicate that CST1-mediated extracellular CatB activity enhances tumor development by preventing cellular senescence. Our findings suggest that antagonists of CST1 or inhibitors of CatB are potential anticancer agents.
authors.affiliation: Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea.|Division of Life Science, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Sang-Seok
authors.initials: SS
authors.lastname: Oh
authors.affiliation: Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Soojong
authors.initials: S
authors.lastname: Park
authors.affiliation: Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Ki-Won
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Hamadi
authors.initials: H
authors.lastname: Madhi
authors.affiliation: Department of Microbiology, College of Medicine, Inje University, Busan, Republic of Korea.
authors.forename: Sae Gwang
authors.initials: SG
authors.lastname: Park
authors.affiliation: Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
authors.forename: Hee Gu
authors.initials: HG
authors.lastname: Lee
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon, Republic of Korea.
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
authors.affiliation: Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea.|Division of Life Science, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Jiyun
authors.initials: J
authors.lastname: Yoo
authors.affiliation: Division of Applied Life Science (BK21 Plus), Gyeongsang National University, Jinju, Republic of Korea.|Division of Life Science, Gyeongsang National University, Jinju, Republic of Korea.|PMBBRC, Gyeongsang National University, Jinju, Republic of Korea.
authors.forename: Kwang
authors.initials: K
authors.lastname: Dong Kim
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics; D055785:Gene Knockdown Techniques; D006003:Glycogen / Q000096:biosynthesis* / Q000235:genetics; D006006:Glycogen Synthase / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D055333:Salivary Cystatins / Q000235:genetics / Q000378:metabolism*
chemical_list: C525171:CST1 protein, human; D009363:Neoplasm Proteins; D055333:Salivary Cystatins; D006003:Glycogen; D006006:Glycogen Synthase; C533912:CTSB protein, human; D002401:Cathepsin B