Recombinant cathepsin S propeptide attenuates cell invasion by inhibition of cathepsin L-like proteases in tumor microenvironment.

Abstract

Human cathepsin L along with cathepsin S, K, and V are collectively known as cathepsin L-like proteases due to their high homology. The overexpression and aberrant activity of each of these proteases has been implicated in tumorigenesis. These proteases contain propeptide domains that can potently inhibit both their cognate protease and other proteases within the cathepsin L-like subfamily. In this investigation, we have produced the cathepsin S propeptide recombinantly and have shown that it is a potent inhibitor of the peptidolytic, elastinolytic, and gelatinolytic activities of the cathepsin L-like proteases. In addition, we show that this peptide is capable of significantly attenuating tumor cell invasion in a panel of human cancer cell lines. Furthermore, fusion of an IgG Fc-domain to the COOH terminus of the propeptide resulted in a chimeric protein with significantly enhanced ability to block tumor cell invasion. This Fc fusion protein exhibited enhanced stability in cell-based assays in comparison with the unmodified propeptide species. This approach for the combined inhibition of the cathepsin L-like proteases may prove useful for the further study in cancer and other conditions where their aberrant activity has been implicated. Furthermore, this strategy for simultaneous inhibition of multiple cysteine cathepsins may represent the basis for novel therapeutics to attenuate tumorigenesis.

• Authors: Roberta E Burden, Philip Snoddy, Richard J Buick, James A Johnston, Brian Walker, Christopher J Scott
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 7 Issue 3 Pg. 538-47 (Mar 2008) ISSN: 1535-7163 [Print] United States
• PMID: 18347141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cysteine Proteinase Inhibitors
• DNA Primers
• Recombinant Proteins
• Cathepsins
• Cysteine Endopeptidases
• CTSL protein, human
• Cathepsin L
• cathepsin S

Topics

• Base Sequence
• Cathepsin L
• Cathepsins (antagonists & inhibitors, chemistry, metabolism)
• Cell Line, Tumor
• Cysteine Endopeptidases (metabolism)
• Cysteine Proteinase Inhibitors (pharmacology)
• DNA Primers
• Humans
• Recombinant Proteins (chemistry, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction