Abstract
Proteases are involved in many aspects of tumor progression, including cell survival and proliferation, escape from immune surveillance, cell adhesion and migration, remodeling and invasion of the extracellular matrix. Several lysosomal cysteine proteases have been cloned and shown to be overexpressed in cancer; yet, despite the great potential for development of novel therapeutics, we still know little about the regulation of their proteolytic activity. Cystatins such as cystatin M are potent endogenous protein inhibitors of lysosomal cysteine proteases. Cystatin M is expressed in normal and premalignant human epithelial cells, but not in many cancer cell lines. Here, we examined the effects of cystatin M expression on malignant properties of human breast carcinoma MDA-MB-435S cells. Cystatin M was found to significantly reduce in vitro: cell proliferation, migration, Matrigel invasion, and adhesion to endothelial cells. Reduction of cell proliferation and adhesion to an endothelial cell monolayer were both independent of the inhibition of lysosomal cysteine proteases. In contrast, cell migration and matrix invasion seemed to rely on lysosomal cysteine proteases, as both recombinant cystatin M and E64 were able to block these processes. This study provides the first evidence that cystatin M may play important roles in safeguarding against human breast cancer.
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Acknowledgements
We wish to acknowledge the generous gift of human melanoma cell lines from Dr Meenhard Herlyn (The Wistar Institute, Philadelphia, PA, USA) and of cystatin C antibodies from Dr Magnus Abrahamson (University of Lund, Lund, Sweden). Our warmest thanks are also due to Dr Avraham Raz, for his lively input throughout this work. Part of this study was supported by a Virtual Discovery Grant (DK) from the Barbara Ann Karmanos Cancer Institute and Research Grants CA91785 (DK) and CA36481 (BFS) from the National Cancer Institute.
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Shridhar, R., Zhang, J., Song, J. et al. Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells. Oncogene 23, 2206–2215 (2004). https://doi.org/10.1038/sj.onc.1207340
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DOI: https://doi.org/10.1038/sj.onc.1207340
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