Stefin B deficiency reduces tumor growth via sensitization of tumor cells to oxidative stress in a breast cancer model

• Published in: Oncogene Vol. 33; no. 26; pp. 3392 - 3400
• Main Authors: Butinar, M, Prebanda, M T, Rajković, J, Jerič, B, Stoka, V, Peters, C, Reinheckel, T, Krüger, A, Turk, V, Turk, B, Vasiljeva, O
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.06.2014; Nature Publishing Group
• Subjects: 631/45/474/1624; 631/67/1347; 631/80/86; Ablation; Angiogenesis; Animals; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Care and treatment; Cathepsins; Cathepsins - antagonists & inhibitors; Cell Biology; Cell death; Cell migration; Cell Movement - genetics; Cell Proliferation; Cystatin B - genetics; Cysteine Proteinase Inhibitors - genetics; Dipeptides - pharmacology; Disease Progression; Enzymatic activity; Enzyme inhibitors; Female; Genetic aspects; Human Genetics; Immunosuppressive Agents - pharmacology; Internal Medicine; Lysosomes - metabolism; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Knockout; Neoplasm Metastasis - genetics; Neovascularization, Pathologic - genetics; Oncology; original-article; Oxidative stress; Oxidative Stress - genetics; Polyomavirus; Properties; Proteolysis; Transgenic mice; Tumor cells; Tumors; stefin; breast cancer; mouse model; cathepsin inhibitor; oxidative stress
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.314

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.