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 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.
Acknowledgments
This work was supported by the Slovenian Research Agency (grant number J4-5529 to J.K.).
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©2016 by De Gruyter
Articles in the same Issue
- Frontmatter
- Research Articles/Short Communications
- Genes and Nucleic Acids
- Acute hypothalamo-pituitary-adrenal axis response to LPS-induced endotoxemia: expression pattern of kinin type B1 and B2 receptors
- Protein Structure and Function
- Crystal structure of cleaved vaspin (serpinA12)
- Semi-purification procedures of prions from a prion-infected brain using sucrose has no influence on the nonenzymatic glycation of the disease-associated prion isoform
- Involvement of loop 5 lysine residues and the N-terminal β-hairpin of the ribotoxin hirsutellin A on its insecticidal activity
- Membranes, Lipids, Glycobiology
- De novo ceramide synthesis is involved in acute inflammation during labor
- Cell Biology and Signaling
- A role for NGF and its receptors TrKA and p75NTR in the progression of COPD
- Proteolysis
- Inhibition of endopeptidase and exopeptidase activity of cathepsin B impairs extracellular matrix degradation and tumour invasion
Articles in the same Issue
- Frontmatter
- Research Articles/Short Communications
- Genes and Nucleic Acids
- Acute hypothalamo-pituitary-adrenal axis response to LPS-induced endotoxemia: expression pattern of kinin type B1 and B2 receptors
- Protein Structure and Function
- Crystal structure of cleaved vaspin (serpinA12)
- Semi-purification procedures of prions from a prion-infected brain using sucrose has no influence on the nonenzymatic glycation of the disease-associated prion isoform
- Involvement of loop 5 lysine residues and the N-terminal β-hairpin of the ribotoxin hirsutellin A on its insecticidal activity
- Membranes, Lipids, Glycobiology
- De novo ceramide synthesis is involved in acute inflammation during labor
- Cell Biology and Signaling
- A role for NGF and its receptors TrKA and p75NTR in the progression of COPD
- Proteolysis
- Inhibition of endopeptidase and exopeptidase activity of cathepsin B impairs extracellular matrix degradation and tumour invasion