Unraveling the role of proteases in cancer.

Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA.
Clinica Chimica Acta (Impact Factor: 2.76). 03/2000; 291(2):113-35. DOI: 10.1016/S0009-8981(99)00224-7
Source: PubMed

ABSTRACT Investigators have been studying the expression and activity of proteases in the final steps of tumor progression, invasion and metastasis, for the past 30 years. Recent studies, however, indicate that proteases are involved earlier in progression, e.g., in tumor growth both at the primary and metastatic sites. Extracellular proteases may co-operatively influence matrix degradation and tumor cell invasion through proteolytic cascades, with individual proteases having distinct roles in tumor growth, invasion, migration and angiogenesis. In this review, we use cathepsin B as an example to examine the involvement of proteases in tumor progression and metastasis. We discuss the effect of interactions among tumor cells, stromal cells, and the extracellular matrix on the regulation of protease expression. Further elucidation of the role of proteases in cancer will allow us to design more effective inhibitors and novel protease-based drugs for clinical use.

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    ABSTRACT: Cathepsin B is a ubiquitously expressed lysosomal cysteine protease that participates in protein turnover within lysosomes. However, its protein and activity levels have been shown to be increased in cancer. Cathepsin B endopeptidase activity is involved in the degradation of extracellular matrix, a process that promotes tumor invasion, metastasis and angiogenesis. Previously, we reported an established antibiotic nitroxoline as a potent and selective inhibitor of cathepsin B. In the present study, we elucidated its anti-tumor properties in in vitro and in vivo tumor models.Tumor and endothelial cell lines with high levels of active cathepsin B were selected for functional analysis of nitroxoline in vitro. Nitroxoline significantly reduced extracellular DQ-collagen IV degradation by all evaluated cancer cell lines using spectrofluorimetry. Nitroxoline also markedly decreased tumor cell invasion monitored in real time and reduced the invasive growth of multicellular tumor spheroids, used as a 3D in vitro model of tumor invasion. Additionally, endothelial tube formation was significantly reduced by nitroxoline in an in vitro angiogenesis assay. Finally, nitroxoline significantly abrogated tumor growth, angiogenesis and metastasis in vivo in LPB fibrosarcoma and MMTV-PyMT breast cancer mouse models. Overall, our results designate nitroxoline as a promising drug candidate for anti-cancer treatment.
    Oncotarget 03/2015; · 6.63 Impact Factor
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    ABSTRACT: The chapter reports structural characteristics and biotechnological applications of proteinaceous protease inhibitors with emphasis on their antifungal and antibacterial activities. Protease inhibition occurs through the formation of a complex between an enzyme and the inhibitory molecule which can interfere in several biological processes such as inflammation, apoptosis, blood clotting and hormone processing pathways. These molecules have been reported as part of defense mechanism of plants against fungal and insect attack. In general, protease inhibitors are able to affect fungi by inhibiting extracellular and/or intracellular proteases that display important roles in nutrition and infection processes since the invasion of host tissue and fungal development depends on the degradation of membrane and/or cell wall proteins. Antifungal trypsin inhibitors may also act directly at level of fungal cell membrane. Protease inhibitors have also been reported as antibacterial agents. This property has been attributed to inhibition of bacterial proteases involved in several physiological processes as well as to interaction between the inhibitor and the cell wall or proteins from plasma membrane leading to changes in cell permeability and inducing the death of bacteria. This chapter also presents methodologies used for evaluation of antifungal and antibacterial activities of several samples, including protease inhibitors. The remarkable ability to affect fungi and bacteria growth stimulates the evaluation of using protease inhibitors in strategies to control microorganisms pathogenic for human and plants.
    Microbial pathogens and strategies for combating them: science, technology and education, Microbiology Book Series – 2013 Edition edited by A. Méndez-Vilas, 05/2013: chapter Protease inhibitors from plants: Biotechnological insights with emphasis on their effects on microbial pathogens: pages 641-649; Formatex Research Centre, C/Zurbaran, 1, 2nd Floor, office 1, 06002 Badajoz, Spain., ISBN: 9788493984397
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    ABSTRACT: Protein- and peptide-drug conjugates hold a promising stance in the delivery of therapeutic agents by providing distinct advantage of improving therapeutic potential of drugs. Recent advancements in the proteomics and recombinant DNA technology, by enabling identification of distinct structural features of proteins and making it feasible to introduce specific functionalities in protein/peptide structure, has made it possible to synthesize high quality protein- and peptide-drug conjugates though a wide variety of coupling techniques. Additionally, use of specialized linkers makes them unique in their in vivo therapeutic application by providing target tissue-specific release of drug. Several protein- and peptide-drug conjugates are currently under clinical trials warranting their huge market potential in near future. Increased understanding in this field will surely enable us to produce high quality protein- and peptide-drug conjugates which will serve therapeutic needs demanded from drug delivery systems in clinical settings. © 2015 Elsevier Inc. All rights reserved.
    01/2015; 98:1-55. DOI:10.1016/bs.apcsb.2014.11.001

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