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A novel cysteine cathepsin inhibitor yields macrophage cell death and mammary tumor regression
- Source :
- Oncogene. 34:6066-6078
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- 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-NH2, 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.
- Subjects :
- Cathepsin
Mice, Inbred BALB C
Cancer Research
Mammary tumor
Macrophages
Autophagy
Cell Polarity
Mammary Neoplasms, Experimental
Cathepsin D
Apoptosis
Biology
Cathepsins
Cell biology
Mice
Oxidative Stress
Cathepsin L1
Cancer cell
Genetics
Animals
Female
Reactive Oxygen Species
Molecular Biology
Cathepsin S
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....7becd0ccae8233647da0072b6bcaf233