Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells.
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.
Shridhar
Ravi
R
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Zhang
Jun
J
Song
Jin
J
Booth
Blake A
BA
Kevil
Christopher G
CG
Sotiropoulou
Georgia
G
Sloane
Bonnie F
BF
Keppler
Daniel
D
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018938:Caco-2 Cells; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D055332:Cystatin M; D015891:Cystatins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007797:Laminin / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism; D014162:Transfection
C525104:CST6 protein, human; D055332:Cystatin M; D015891:Cystatins; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen