title: Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis.
abstract: Cathepsin B is a cysteine proteinase that primarily functions as an endopeptidase within endolysosomal compartments in normal cells. However, during tumoral expansion, the regulation of cathepsin B can be altered at multiple levels, thereby resulting in its overexpression and export outside of the cell. This may suggest a possible role of cathepsin B in alterations leading to cancer progression. The aim of this study was to determine the contribution of intracellular and extracellular cathepsin B in growth, tumorigenesis, and invasion of colorectal cancer (CRC) cells. Results show that mRNA and activated levels of cathepsin B were both increased in human adenomas and in CRCs of all stages. Treatment of CRC cells with the highly selective and non-permeant cathepsin B inhibitor Ca074 revealed that extracellular cathepsin B actively contributed to the invasiveness of human CRC cells while not essential for their growth in soft agar. Cathepsin B silencing by RNAi in human CRC cells inhibited their growth in soft agar, as well as their invasion capacity, tumoral expansion, and metastatic spread in immunodeficient mice. Higher levels of the cell cycle inhibitor p27(Kip1) were observed in cathepsin B-deficient tumors as well as an increase in cyclin B1. Finally, cathepsin B colocalized with p27(Kip1) within the lysosomes and efficiently degraded the inhibitor. In conclusion, the present data demonstrate that cathepsin B is a significant factor in colorectal tumor development, invasion, and metastatic spreading and may, therefore, represent a potential pharmacological target for colorectal tumor therapy.
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors: Benjamin
authors: B
authors: Bian
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors: Sébastien
authors: S
authors: Mongrain
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors: Sébastien
authors: S
authors: Cagnol
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors: Marie-Josée
authors: MJ
authors: Langlois
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors: Jim
authors: J
authors: Boulanger
authors: Gastroenterology Service, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors: Gérald
authors: G
authors: Bernatchez
authors: Gastroenterology Service, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors: Julie C
authors: JC
authors: Carrier
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors: François
authors: F
authors: Boudreau
authors: Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors: Nathalie
authors: N
authors: Rivard
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002401:Cathepsin B / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004151:Dipeptides / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation
chemical_list: C400541:CA 074 methyl ester; D004151:Dipeptides; C533912:CTSB protein, human; D002401:Cathepsin B
keywords: cathepsin B; colorectal cancers; intestinal tumorigenesis; invasion; p27Kip1