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

Oncogene volume 34, pages 6066–6078 (2015)Cite this article

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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.

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Acknowledgements

We thank Dr Michael Berger (The Hebrew University) for providing reagents and advice regarding the project. We would like to acknowledge Boris Turk (Lubljana, Slovenia) for supplying the recombinant cathepsins. This work was supported by the Israel Cancer Research Foundation (ICRF) (to GB, SJS and TG) and the European Research Council (Marie Curie International Reintegration Grant) (to GB).

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Authors and Affiliations

  1. Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    S J Salpeter, E Merquiol, Y Ben-Nun & G Blum

  2. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel

    Y Pozniak & T Geiger

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  1. S J Salpeter
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Correspondence to G Blum.

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Salpeter, S., Pozniak, Y., Merquiol, E. et al. A novel cysteine cathepsin inhibitor yields macrophage cell death and mammary tumor regression. Oncogene 34, 6066–6078 (2015). https://doi.org/10.1038/onc.2015.51

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