New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity

Mitrović, Ana; Senjor, Emanuela; Jukič, Marko; Bolčina, Lara; Prunk, Mateja; Proj, Matic; Nanut, Milica Perišić; Gobec, Stanislav; Kos, Janko

doi:10.1016/j.csbj.2022.08.046

Cited by 5 publications

(1 citation statement)

References 63 publications

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“…To inhibit cathepsin C, H, and L, it is transferred to endo/lysosomes by Asn62 N-linked glycosylation. In the lysosomes cystatin F is converted to a monomer by proteolytic cleavage of the 15-amino-acid N-terminal peptide by cathepsin V [ 27 – 29 ]. It was proposed that glycosylation stabilizes the dimeric form [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

Different glycosylation profiles of cystatin F alter the cytotoxic potential of natural killer cells

Senjor,

Pirro,

Švajger

et al. 2023

Cell. Mol. Life Sci.

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Cystatin F, a cysteine peptidase inhibitor, is a potent modulator of NK cytotoxicity. By inhibiting granule-mediated cytotoxicity pathway, cystatin F induces formation of non-functional NK cell stage, called split-anergy. We show that N-glycosylation determines the localization and cellular function of cystatin F. Cystatin F mostly exhibited high-mannose glycosylation in U-937 cells, both high-mannose and complex glycosylation in NK-92 and primary NKs, and predominantly complex glycosylation in super-charged NKs. Manipulating N-glycosylation with kifunensine increased high-mannose glycosylation of cystatin F and lysosome localisation, which decreased cathepsin C activity and reduced NK cytotoxicity. Mannose-6-phosphate could significantly reduce the internalization of extracellular cystatin F. By comparing NK cells with different cytotoxic potentials, we found that high-mannose cystatin F was strongly associated with lysosomes and cathepsin C in NK-92 cell line. In contrast, in highly cytotoxic super-charged NKs, cystatin F with complex glycosylation was associated with the secretory pathway and less prone to inhibit cathepsin C. Modulating glycosylation to alter cystatin F localisation could increase the cytotoxicity of NK cells, thereby enhancing their therapeutic potential for treating cancer patients. Graphical abstract

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Section: Introductionmentioning

confidence: 99%

Different glycosylation profiles of cystatin F alter the cytotoxic potential of natural killer cells

Senjor,

Pirro,

Švajger

et al. 2023

Cell. Mol. Life Sci.

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Cathepsin inhibitors nitroxoline and its derivatives inhibit SARS-CoV-2 infection

et al. 2023

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Cathepsin V regulates cell cycle progression and histone stability in the nucleus of breast cancer cells

Sereesongsaeng,

Burrows,

Scott

et al. 2023

Front. Pharmacol.

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Introduction: We previously identified that Cathepsin V (CTSV) expression is associated with poor prognosis in ER+ breast cancer, particularly within the Luminal A subtype. Examination of the molecular role of the protease within Luminal A tumours, revealed that CTSV promotes tumour cell invasion and proliferation, in addition to degradation of the luminal transcription factor, GATA3, via the proteasome.Methods: Cell line models expressing CTSV shRNA or transfected to overexpress CTSV were used to examine the impact of CTSV on cell proliferation by MTT assay and flow cytometry. Western blotting analysis was used to identify the impact of CTSV on histone and chaperone protein expression. Cell fractionation and confocal microscopy was used to illustrate the presence of CTSV in the nuclear compartment.Results: In this work we have identified that CTSV has an impact on breast cancer cell proliferation, with CTSV depleted cells exhibiting delayed progression through the G2/M phase of the cell cycle. Further investigation has revealed that CTSV can control nuclear expression levels of histones H3 and H4 via regulating protein expression of their chaperone sNASP. We have discovered that CTSV is localised to the nuclear compartment in breast tumour cells, mediated by a bipartite nuclear localisation signal (NLS) within the CTSV sequence and that nuclear CTSV is required for cell cycle progression and histone stability in breast tumour cells.Discussion: Collectively these findings support the hypothesis that targeting CTSV may have utility as a novel therapeutic target in ER+ breast cancer by impairing cell cycle progression via manipulating histone stabilisation.

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New inhibitors of cathepsin V impair tumor cell proliferation and elastin degradation and increase immune cell cytotoxicity

Cited by 5 publications

References 63 publications

Different glycosylation profiles of cystatin F alter the cytotoxic potential of natural killer cells

Different glycosylation profiles of cystatin F alter the cytotoxic potential of natural killer cells

Cathepsin inhibitors nitroxoline and its derivatives inhibit SARS-CoV-2 infection

Cathepsin V regulates cell cycle progression and histone stability in the nucleus of breast cancer cells

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