Unraveling the role of proteases in cancer

Wayne State University, Detroit, Michigan, United States
Clinica Chimica Acta (Impact Factor: 2.82). 03/2000; 291(2):113-35. DOI: 10.1016/S0009-8981(99)00224-7
Source: PubMed


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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Available from: Mamoun Ahram
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    • "The low activity of these enzymes in blood is because of presence of endogenous inhibitors and unfavorably high pH value of blood as compared to lysosomes [40]. Peptide-based linkers are completely hydrolyzed into the tumor mass due to the presence of proteases and release the potent drug [41]. Peptide linkers have been extensively used for the development of ADCs using different potent drugs [22,42–44]. "

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    • "ECM provides an important physical barrier against tumour spread and its proteolysis, mediated by tumour cells and infiltrated macrophages, fibroblasts and endothelial cells creates a pathway for tumour and endothelial cells to migrate and invade the degraded matrix (Premzl et al., 2003, 2006; Mirković et al., 2009; Jevnikar et al., 2012). ECM degradation by cathepsin B occurs extracellularly by the secreted and membrane-associated cathepsin B (Koblinski et al., 2000) and intracellularly in lysosomes after endocytosis of partially degraded ECM components (Premzl et al., 2003; Mohamed and Sloane, 2006). Employing the same mechanism, cathepsin B also contributes to neovascularisation of tumours (Premzl et al., 2006; Cavallo-Medved et al., 2009), which it also promotes by proteolytic inactivation of metalloprotease inhibitors, TIMP-1 and TIMP-2 (Kostoulas et al., 1999). "
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    ABSTRACT: Cathepsin B is a lysosomal cysteine protease that is implicated in a number of physiological processes, including protein turnover in lysosomes. Changes in its expression are associated with a variety of pathological processes, including cancer. Due to the structural feature, termed the occluding loop, cathepsin B differs from other cysteine proteases in possessing both, endopeptidase and exopeptidase activity. Here we investigated the impact of both cathepsin B activities on intracellular and extracellular collagen IV degradation and tumour cell invasion using new selective synthetic inhibitors, 2-{[(8-hydroxy-5-nitroquinoline-7- yl)methyl]amino}-acetonitrile (1), 8-(4-methylpiperidin-1-yl)-5-nitroquinoline (2) and 7-[(4-methylpiperidin-1yl)methyl]-5-nitroquinolin-8-ol (3). All three compounds (5 μᴍ) reduced extracellular degradation of collagen IV by MCF-10A neoT cells by 45-70% as determined by spectrofluorimetry and they (50 μᴍ) attenuated intracellular collagen IV degradation by 40-60% as measured with flow cytometry. Furthermore, all three compounds (5 μᴍ) impaired MCF-10A neoT cell invasion by 40-80% as assessed by measuring electrical impedance in real time. Compounds 1 and 3 (5 μᴍ), but not compound 2, significantly reduced the growth of MMTV-PyMT multicellular tumour spheroids. Collectively, these data suggest that the efficient strategy to impair harmful cathepsin B activity in tumour progression may include simultaneous and potent inhibition of cathepsin B endopeptidase and exopeptidase activities.
    No preview · Article · Nov 2015 · Biological Chemistry
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    • "In this context, nanocarriers should release their drug payload only in response to specific physiological changes naturally occurring within tumors, such as the presence of high concentrations of matrix metalloproteases (MMPs) (Basel et al., 2011; Nagase and Woessner, Jr., 1999; Kugler, 1999; Sawant et al., 2006). MMPs are proteolytic enzymes overexpressed in tumors, which are involved in a number of biological mechanisms and catalytic activities related with tumor progression (Koblinski et al., 2000; Zucker, 1988). In particular, MMP2 (also known as gelatinase A; Mw: 72 kDa) hydrolyzes type IV collagen, which is a major constituent of tumor extracellular matrix (ECM), thus resulting in enhanced tumor progression (Klein et al., 2004), invasion and angiogenesis (Holle et al., 2003). "
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