title: Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model.
abstract: Lysosomal cysteine cathepsins contribute to proteolytic events promoting tumor growth and metastasis. Their enzymatic activity, however, is tightly regulated by endogenous inhibitors. To investigate the role of cathepsin inhibitor stefin B (Stfb) in mammary cancer, Stfb null mice were crossed with transgenic polyoma virus middle T oncogene (PyMT) breast cancer mice. We show that ablation of Stfb resulted in reduced size of mammary tumors but did not affect their rate of metastasis. Importantly, decrease in tumor growth was correlated with an increased incidence of dead cell islands detected in tumors of Stfb-deficient mice. Ex vivo analysis of primary PyMT tumor cells revealed no significant effects of ablation of Stfb expression on proliferation, angiogenesis, migration and spontaneous cell death as compared with control cells. However, upon treatment with the lysosomotropic agent Leu-Leu-OMe, cancer cells lacking Stfb exhibited a significantly higher sensitivity to apoptosis. Moreover, Stfb-ablated tumor cells were significantly more prone to cell death under increased oxidative stress. These results indicate an in vivo role for Stfb in protecting cancer cells by promoting their resistance to oxidative stress and to apoptosis induced through the lysosomal pathway.
authors: 1] Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia [2] Jožef Stefan International Postgraduate School, Ljubljana, Slovenia.
authors: M
authors: M
authors: Butinar
authors: Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia.
authors: M T
authors: MT
authors: Prebanda
authors: 1] Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia [2] Jožef Stefan International Postgraduate School, Ljubljana, Slovenia.
authors: J
authors: J
authors: Rajković
authors: 1] Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia [2] Jožef Stefan International Postgraduate School, Ljubljana, Slovenia.
authors: B
authors: B
authors: Jerič
authors: 1] Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia [2] Jožef Stefan International Postgraduate School, Ljubljana, Slovenia.
authors: V
authors: V
authors: Stoka
authors: Institute of Molecular Medicine and Cell Research, BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors: C
authors: C
authors: Peters
authors: Institute of Molecular Medicine and Cell Research, BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors: T
authors: T
authors: Reinheckel
authors: Institut für Experimentelle Onkologie und Therapieforschung des Klinikums rechts der Isar, Technische Universität München, München, Germany.
authors: A
authors: A
authors: Krüger
authors: 1] Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia [2] Jožef Stefan International Postgraduate School, Ljubljana, Slovenia [3] Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Ljubljana, Slovenia.
authors: V
authors: V
authors: Turk
authors: 1] Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia [2] Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Ljubljana, Slovenia [3] Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.
authors: B
authors: B
authors: Turk
authors: 1] Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia [2] Jožef Stefan International Postgraduate School, Ljubljana, Slovenia.
authors: O
authors: O
authors: Vasiljeva
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002403:Cathepsins / Q000037:antagonists & inhibitors; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D055313:Cystatin B / Q000235:genetics*; D015853:Cysteine Proteinase Inhibitors / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D018450:Disease Progression; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics*
chemical_list: C524992:Cstb protein, mouse; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D007166:Immunosuppressive Agents; C045139:leucyl-leucine-methyl ester; D055313:Cystatin B; D002403:Cathepsins