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Research Articles: Therapeutics, Targets, and Development

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

¹ School of Pharmacy and ² Centre for Cancer Research and Cell Biology, Queen's University of Belfast; and ³ Fusion Antibodies Ltd., Belfast, Northern Ireland

Requests for reprints: Christopher J. Scott, School of Pharmacy, Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland. Phone: 440-2890972350. E-mail: c.scott{at}qub.ac.uk

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]

Grant support: Department of Education and Learning, Northern Ireland and Fusion Antibodies Ltd. Co-Operative Awards in Science and Technology Studentship (R.E. Burden).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/ 3/07; revised 11/ 8/07; accepted 1/21/08.