Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells.

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.

• Authors: Ravi Shridhar, Jun Zhang, Jin Song, Blake A Booth, Christopher G Kevil, Georgia Sotiropoulou, Bonnie F Sloane, Daniel Keppler
• Journal: Oncogene (Oncogene) Vol. 23 Issue 12 Pg. 2206-15 (Mar 18 2004) ISSN: 0950-9232 [Print] England
• PMID: 14676833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CST6 protein, human
• Cystatin M
• Cystatins
• Drug Combinations
• Laminin
• Proteoglycans
• matrigel
• Collagen

Topics

• Breast Neoplasms (metabolism, pathology)
• Caco-2 Cells
• Carcinoma, Ductal, Breast (metabolism, pathology)
• Cell Adhesion (drug effects)
• Cell Division (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Collagen (metabolism)
• Cystatin M
• Cystatins (genetics, metabolism, pharmacology)
• Drug Combinations
• Endothelium, Vascular (drug effects, metabolism)
• HT29 Cells
• Humans
• Laminin (metabolism)
• Neoplasm Invasiveness
• Phenotype
• Proteoglycans (metabolism)
• Transfection