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. [Mol Cancer Ther 2008;7(3):538 -47]

Heparin Enhances Serpin Inhibition of the Cysteine Protease Cathepsin L

“…Cathepsin L is a widely expressed cysteine protease with a major role in lysosomal proteolysis, protein processing, matrix degradation, and tissue remodeling, and it has been linked to the invasive phenotype in many cancers (24,25). Inhibition of cathepsin L activity by synthetic inhibitors and by the cathepsin S propeptide can reduce invasiveness of a number of human cancer cell lines (42), and prevention of cathepsin L secretion by introducing an overexpressed intracellular anticathepsin single chain variable antibody fragment dramatically reduced melanoma cell metastasis (43). We propose that SCCA-1 and heparin may combine to facilitate an endogenous mechanism for regulation of extracellular cathepsin activity and cathepsin-mediated metastasis.…”

Radiation‐induced cathepsin S is involved in radioresistance

“…In spite of this, it has been reported that CatS is overexpressed in many cancer cells and tissues, 22,23 and recently developed radiation treatment technology is able to focus the radiation dose on the area affected by the cancer so that it does not impact unaffected cells. 24 Therefore, given the recent interest in the role that CatS regulation plays in several physiological and pathological processes, radiation-induced CatS expression may give rise to novel therapeutic strategies. 6 -A model illustrating the role of CatS in radiation response.…”

miR-31 Dysregulation in Cystic Fibrosis Airways Contributes to Increased Pulmonary Cathepsin S Production

“…Previous work indicates that CTSS may also play a role in the diminution of the lung's antimicrobial defenses thereby favoring conditions for bacterial infection (13,14,23). Furthermore, given its potent elastinolytic activity (17)(18)(19)(20)53), it is possible that CTSS may play a role in tissue damage and remodeling present in early CF (2, 3, 6, 7), an increasingly recognized clinical finding over the last 5 years. In addition, the presence of elevated CTSS in the CF airways may explain, in part, why previous therapeutic approaches to protease neutralization in the CF lung, which have not taken elevated CTSS activity into account, have not been entirely successful to date.…”