title: Cysteine cathepsin activity suppresses osteoclastogenesis of myeloid-derived suppressor cells in breast cancer.
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.
authors: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.|Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Melbourne, Australia.
authors: Laura E
authors: LE
authors: Edgington-Mitchell
authors: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.|Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.
authors: Jai
authors: J
authors: Rautela
authors: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors: Hendrika M
authors: HM
authors: Duivenvoorden
authors: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors: Krishnath M
authors: KM
authors: Jayatilleke
authors: Department of Pathology, Stanford University School of Medicine, California, USA.
authors: Wouter A
authors: WA
authors: van der Linden
authors: Department of Tumour Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors: Martijn
authors: M
authors: Verdoes
authors: Department of Pathology, Stanford University School of Medicine, California, USA.
authors: Matthew
authors: M
authors: Bogyo
authors: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia.
authors: Belinda S
authors: BS
authors: Parker
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary; D056668:Cathepsin L / Q000737:chemistry; D002403:Cathepsins / Q000378:metabolism*; D002454:Cell Differentiation; D002469:Cell Separation; D003545:Cysteine / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000737:chemistry; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D022423:Myeloid Cells / Q000166:cytology*; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology; D000099240:Asparaginyl Endopeptidase
chemical_list: D056668:Cathepsin L; D002403:Cathepsins; D003545:Cysteine; D003546:Cysteine Endopeptidases; D000099240:Asparaginyl Endopeptidase
keywords: breast cancer metastasis; cathepsin; cysteine protease; myeloid-derived suppressor cell; osteoclast