Novel Bi- and Trifunctional Inhibitors of Tumor-Associated Proteolytic Systems
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J. Krol
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.
Copyright © 2003 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
- Protein Prenyltransferases: Anchor Size, Pseudogenes and Parasites
- Redox Regulation of Cell Growth and Cell Death
- Are Histones the Targets for Flavan-3-ols (Catechins) in Nuclei?
- Exploring the Role of 5’ Alternative Splicing and of the 3’-Untranslated Region of Cathepsin B mRNA
- Interaction of Maize Chromatin-Associated HMG Proteins with Mononucleosomes: Role of Core and Linker Histones
- Transcriptional Silencing of the TFPI-2 Gene by Promoter Hypermethylation in Choriocarcinoma Cells
- Solubilisation and Properties of the Sialate-4-O-Acetyltransferase from Guinea Pig Liver
- A Peroxidase from Lepista irina Cleaves β,β-Carotene to Flavor Compounds
- Physarum polycephalum Expresses a Dihydropteridine Reductase with Selectivity for Pterin Substrates with a 6-(1', 2-Dihydroxypropyl) Substitution
- Effects of Hydrogen Peroxide on Bovine Leukemia Virus Expression
- Ovarian Cancer Cell Proliferation and Motility Is Induced by Engagement of Integrin αvβ3/Vitronectin Interaction
- Novel Bi- and Trifunctional Inhibitors of Tumor-Associated Proteolytic Systems
- Inhibition of Intraperitoneal Tumor Growth of Human Ovarian Cancer Cells by Bi- and Trifunctional Inhibitors of Tumor-Associated Proteolytic Systems
- Expression of High Molecular Weight Cysteine Proteinase Inhibitor in Ovarian Cancer Tissues: Regulation of Cathepsin B Expression by Placental CPI
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