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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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IMPACT FACTOR 2016: 3.273

CiteScore 2016: 3.01

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Source Normalized Impact per Paper (SNIP) 2015: 0.751

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1437-4315
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Volume 384, Issue 7 (Jul 2003)

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Novel Bi- and Trifunctional Inhibitors of Tumor-Associated Proteolytic Systems

J. Krol / S. Sato / P. Rettenberger / I. Assfalg-Machleidt / M. Schmitt / V. Magdolen / U. Magdolen
Published Online: 2005-06-01 | DOI: https://doi.org/10.1515/BC.2003.121

Abstract

Serine proteases, cysteine proteases, and matrix metalloproteinases (MMPs) are involved in cancer cell invasion and metastasis. Recently, a recombinant bifunctional inhibitor (chCys-uPA19-31) directed against cysteine proteases and the urokinase-type plasminogen activator (uPA)/plasmin serine protease system was generated by introducing the uPA receptor (uPAR)-binding site of uPA into chicken cystatin (chCysWT). In the present study, we designed and recombinantly produced multifunctional inhibitors also targeting MMPs. The inhibitors comprise the Nterminal inhibitory domain of human TIMP-1 (tissue inhibitor of matrix metalloproteinase-1) or TIMP-3, fused to chCys-uPA19-31 or chCysWT. As demonstrated by various techniques, these fusion proteins effectively interfere with all three targeted protease systems. In in vitro Matrigel invasion assays, the addition of recombinant inhibitors strongly reduced invasion of ovarian cancer cells (OV-MZ-6#8). Additionally, OV-MZ 6#8 cells were stably transfected with expression plasmids encoding the various inhibitors. Synthesis and secretion of the inhibitors was verified by a newly developed ELISA, which selectively detects the recombinant proteins. Invasive capacity of inhibitorproducing cells was significantly reduced compared to vector-transfected control cells. Thus, these novel, compact, and small-size inhibitors directed against up to three different tumor-associated proteolytic systems may represent promising agents for prevention of tumor cell migration and metastasis.

About the article

Published Online: 2005-06-01

Published in Print: 2003-07-15



Citation Information: Biological Chemistry, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2003.121. Export Citation

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