A novel cysteine cathepsin inhibitor yields macrophage cell death and mammary tumor regression

• Published in: Oncogene 2015-12, Vol.34 (50), p.6066-6078
• Main Authors: Salpeter, S J, Pozniak, Y, Merquiol, E, Ben-Nun, Y, Geiger, T, Blum, G
• Format: Article
• Language: English
• Subjects: 13/31; 14/34; 14/63; 45/77; 631/67/1059/99; 64/60; 82/58; 96/2; Animals; Apoptosis; Autophagy; Breast cancer; Cancer; Care and treatment; Cathepsins; Cathepsins - antagonists & inhibitors; Cathepsins - physiology; Cell Biology; Cell death; Cell Polarity; Cellular biology; Cysteine; Female; Health aspects; Human Genetics; Internal Medicine; Macrophages; Macrophages - drug effects; Macrophages - physiology; Mammary gland; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Medicine; Medicine & Public Health; Methods; Mice; Mice, Inbred BALB C; Molecular targeted therapy; Oncology; original-article; Oxidative Stress; Phagocytosis; Reactive oxygen species; Reactive Oxygen Species - metabolism; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.51

Although cysteine cathepsins have been identified as key regulators of cancer growth, their specific role in tumor development remains unclear. Recent studies have shown that high activity levels of tumor cathepsins are primarily a result of increased cathepsin activity in cancer-promoting tumor-associated macrophages (TAMs). To further investigate the role of cysteine cathepsin activity in normal and polarized macrophages, we established in vitro and in vivo models of macrophage differentiation and polarization and used a novel cysteine cathepsin inhibitor, GB111-NH 2 , to block the activity of cathepsins B, L and S. Here we show that in vitro, cysteine cathepsin inhibition yields both apoptosis and proliferation of macrophages, owing to increased oxidative stress. Proteomic analysis of cathepsin- inhibited macrophages demonstrates inhibition of autophagy, suggesting a likely cause of elevated reactive oxygen species (ROS) levels. In vivo models of mammary cancer further show that cathepsin inhibition yields TAM death owing to increased ROS levels. Strikingly, apoptosis in TAMs yields a seemingly cell non-autonomous death of neighboring cancer cells, and regression of the primary growth. These results show that cysteine cathepsin inhibitors can specifically trigger macrophage cell death and may function as an effective anticancer therapy in tumors with high levels of TAMs.