ArticleThe Journal of biological chemistry2013
Cystatin C properties crucial for uptake and inhibition of intracellular target enzymes.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- Unravelling the Significance of Cystatin C and Bunina Bodies in Amyotrophic Lateral Sclerosis Pathogenesis.Neuropathology and applied neurobiology · 2026Review
- Cystatin C prevents tissue injury after lung transplantation.Life science alliance · 2026Article
- Age-dependent changes on fractalkine forms and their contribution to neurodegenerative diseases.Frontiers in molecular neuroscience · 2023Review
- Cystatin C Deficiency Increases LPS-Induced Sepsis and NLRP3 Inflammasome Activation in Mice.Cells · 2021Article
- Externally added cystatin C reduces growth of A375 melanoma cells by increasing cell cycle time.FEBS open bio · 2021Article
- Review
- A Cystatin C Cleavage ELISA Assay as a Quality Control Tool for Determining Sub-Optimal Storage Conditions of Cerebrospinal Fluid Samples in Alzheimer's Disease Research.Journal of Alzheimer's disease : JAD · 2021Article
- Secreted cystatins decrease proliferation and enhance apoptosis of human leukemic cells.FEBS open bio · 2020Article
- Proteolysis is the most fundamental property of malignancy and its inhibition may be used therapeutically (Review).International journal of molecular medicine · 2019Review
- Proteomic Profiling of Primary Human Acute Myeloid Leukemia Cells Does Not Reflect Their Constitutive Release of Soluble Mediators.Proteomes · 2018Article
- Involvement of cystatin C in immunity and apoptosis.Immunology letters · 2018Review
- Low-level internalization of cystatin E/M affects legumain activity and migration of melanoma cells.The Journal of biological chemistry · 2017Article
- Article
- Cystatin C in aging and in Alzheimer's disease.Ageing research reviews · 2016Review
- Prognostic value of cystatin C in patients with nasopharyngeal carcinoma: a retrospective study of 1063 patients.Clinics (Sao Paulo, Brazil) · 2016Article
- Evidence of Alternative Cystatin C Signal Sequence Cleavage Which Is Influenced by the A25T Polymorphism.PloS one · 2016Article
- Proteolysis mediated by cysteine cathepsins and legumain-recent advances and cell biological challenges.Protoplasma · 2015Review
- Expression of Cystatin SN significantly correlates with recurrence, metastasis, and survival duration in surgically resected non-small cell lung cancer patients.Scientific reports · 2015Article
- Cystatin C protects neuronal cells against mutant copper-zinc superoxide dismutase-mediated toxicity.Cell death & disease · 2014Article
- Removal and rebound kinetics of cystatin C in high-flux hemodialysis and hemodiafiltration.Clinical journal of the American Society of Nephrology : CJASN · 2014Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
To elucidate the molecular requirements for cancer cell internalization of the extracellular cysteine protease inhibitor cystatin C, 12 variants of the protein were produced and used for uptake experiments in MCF-7 cells. Variants with alterations in the cysteine cathepsin binding region ((Δ1-10)-, K5A-, R8G-, (R8G,L9G,V10G)-, (R8G,L9G,V10G,W106G)-, and W106G-cystatin C) were internalized to a very low extent compared with the wild-type inhibitor. Substitutions of N39 in the legumain binding region (N39K- and N39A-cystatin C) decreased the internalization and (R24A,R25A)-cystatin C, with substitutions of charged residues not involved in enzyme inhibition, was not taken up at all. Two variants, W106F- and K75A-cystatin C, showed that the internalization can be positively affected by engineering of the cystatin molecule. Microscopy revealed vesicular co-localization of internalized cystatin C with the lysosomal marker proteins cathepsin D and legumain. Activities of both cysteine cathepsins and legumain, possible target enzymes associated with cancer cell invasion and metastasis, were down-regulated in cell homogenates following cystatin C uptake. A positive effect on regulation of intracellular enzyme activity by a cystatin variant selected from uptake properties was illustrated by incubating cells with W106F-cystatin C. This resulted in more efficient down-regulation of intracellular legumain activity than when cells were incubated with wild-type cystatin C. Uptake experiments in prostate cancer cells corroborated that the cystatin C internalization is generally relevant and confirmed an increased uptake of W106F-cystatin C, in PC3 cells. Thus, intracellular cysteine proteases involved in cancer-promoting processes might be controled by cystatin uptake.
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