Cysteine cathepsin activity suppresses osteoclastogenesis of myeloid-derived suppressor cells in breast cancer

Abstract

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Laura E. Edgington-Mitchell1, 5, Jai Rautela1, 2, Hendrika M. Duivenvoorden1, Krishnath M. Jayatilleke1, Wouter A. van der Linden3, Martijn Verdoes4, Matthew Bogyo3, Belinda S. Parker1 1Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia 2Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia 3Department of Pathology, Stanford University School of Medicine, California, USA 4Department of Tumour Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands 5Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, Australia Correspondence to: Belinda S. Parker, e-mail: Belinda.Parker@latrobe.edu.au Laura E. Edgington-Mitchell, e-mail: Laura.Edgington-Mitchell@monash.edu Keywords: cysteine protease, cathepsin, myeloid-derived suppressor cell, breast cancer metastasis, osteoclast Received: May 17, 2015 Accepted: July 06, 2015 Published: July 17, 2015 ABSTRACT Cysteine cathepsin proteases contribute to many normal cellular functions, and their aberrant activity within various cell types can contribute to many diseases, including breast cancer. It is now well accepted that cathepsin proteases have numerous cell-specific functions within the tumor microenvironment that function to promote tumor growth and invasion, such that they may be valid targets for anti-metastatic therapeutic approaches. Using activity-based probes, we have examined the activity and expression of cysteine cathepsins in a mouse model of breast cancer metastasis to bone. In mice bearing highly metastatic tumors, we detected abundant cysteine cathepsin expression and activity in myeloid-derived suppressor cells (MDSCs). These immature immune cells have known metastasis-promoting roles, including immunosuppression and osteoclastogenesis, and we assessed the contribution of cysteine cathepsins to these functions. Blocking cysteine cathepsin activity with multiple small-molecule inhibitors resulted in enhanced differentiation of multinucleated osteoclasts. This highlights a potential role for cysteine cathepsin activity in suppressing the fusion of osteoclast precursor cells. In support of this hypothesis, we found that expression and activity of key cysteine cathepsins were downregulated during MDSC-osteoclast differentiation. Another cysteine protease, legumain, also inhibits osteoclastogenesis, in part through modulation of cathepsin L activity. Together, these data suggest that cysteine protease inhibition is associated with enhanced osteoclastogenesis, a process that has been implicated in bone metastasis.