Inhibition of endopeptidase and exopeptidase activity of cathepsin B impairs extracellular matrix degradation and tumour invasion
| Autor: | Izidor Sosič, Bojana Mirković, Janko Kos, Stanislav Gobec, Ana Mitrović |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cell Survival Clinical Biochemistry Breast Neoplasms Biochemistry Cathepsin B Structure-Activity Relationship 03 medical and health sciences Piperidines Tumor Cells Cultured Extracellular Aminoacetonitrile Humans Neoplasm Invasiveness Protease Inhibitors Molecular Biology Cathepsin Exopeptidase activity Dose-Response Relationship Drug Molecular Structure biology Chemistry Nitroquinolines Exopeptidase Cysteine protease Endopeptidase Extracellular Matrix 030104 developmental biology biology.protein Female Extracellular Matrix Degradation |
| Zdroj: | Biological Chemistry. 397:165-174 |
| ISSN: | 1437-4315 1431-6730 |
| DOI: | 10.1515/hsz-2015-0236 |
| Popis: | 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 μm) reduced extracellular degradation of collagen IV by MCF-10A neoT cells by 45–70% as determined by spectrofluorimetry and they (50 μm) attenuated intracellular collagen IV degradation by 40-60% as measured with flow cytometry. Furthermore, all three compounds (5 μm) impaired MCF-10A neoT cell invasion by 40–80% as assessed by measuring electrical impedance in real time. Compounds 1 and 3 (5 μm), 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. |
| Databáze: | OpenAIRE |
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