Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells
| Autor: | Robert Vidmar, Aleksander Krajnc, Vito Turk, Anders Grubb, Marko Fonović, Miha Butinar, Janja Završnik, Olga Vasiljeva, Boris Turk, Mojca Trstenjak Prebanda |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
mouse model Cell medicine.disease_cause 03 medical and health sciences breast cancer 0302 clinical medicine cathepsin inhibitor cystatin C medicine Cathepsin Mammary tumor biology business.industry Cancer medicine.disease 030104 developmental biology medicine.anatomical_structure Oncology Cystatin C 030220 oncology & carcinogenesis Knockout mouse Immunology Cancer research biology.protein Signal transduction business Carcinogenesis Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Janja Zavrsnik 1, 2 , Miha Butinar 1 , Mojca Trstenjak Prebanda 1 , Aleksander Krajnc 1, 2 , Robert Vidmar 1, 2 , Marko Fonovic 1, 4 , Anders Grubb 3 , Vito Turk 1, 2 , Boris Turk 1, 4, 5 and Olga Vasiljeva 1, 6 1 Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, SI-1000 Ljubljana, Slovenia 2 Jozef Stefan International Postgraduate School, Sl-1000 Ljubljana, Slovenia 3 Department of Clinical Chemistry, Laboratory Medicine, University Hospital, SE-22185 Lund, Sweden 4 Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, SI-1000 Ljubljana, Slovenia 5 Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia 6 Current address: CytomX Therapeutics, Inc., South San Francisco, CA 94080, USA Correspondence to: Olga Vasiljeva, email: olga.vasiljeva@gmail.com Keywords: cathepsin inhibitor, cystatin C, breast cancer, mouse model Received: December 09, 2016 Accepted: March 22, 2017 Published: April 24, 2017 ABSTRACT Cysteine cathepsins are proteases that, in addition to their important physiological functions, have been associated with multiple pathologies, including cancer. Cystatin C (CstC) is a major endogenous inhibitor that regulates the extracellular activity of cysteine cathepsins. We investigated the role of cystatin C in mammary cancer using CstC knockout mice and a mouse model of breast cancer induced by expression of the polyoma middle T oncoprotein (PyMT) in the mammary epithelium. We showed that the ablation of CstC reduced the rate of mammary tumor growth. Notably, a decrease in the proliferation of CstC knockout PyMT tumor cells was demonstrated ex vivo and in vitro , indicating a role for this protease inhibitor in signaling pathways that control cell proliferation. An increase in phosphorylated p-38 was observed in CstC knockout tumors, suggesting a novel function for cystatin C in cancer development, independent of the TGF-β pathway. Moreover, proteomic analysis of the CstC wild-type and knockout PyMT primary cell secretomes revealed a decrease in the levels of 14-3-3 proteins in the secretome of knock-out cells, suggesting a novel link between cysteine cathepsins, cystatin C and 14-3-3 proteins in tumorigenesis, calling for further investigations. |
| Databáze: | OpenAIRE |
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