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Cathepsin B and Cathepsin Z tumor secretome of murine breast cancers

ABSTRACT: MS-based proteomics study of the cancer secretome and tumor interstitial fluid of tumor cell/macrophage co-cultures and breast tumors in cells and mice lacking both cathepsin B and cathepsin Z

INSTRUMENT(S): QSTAR, Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Suspension Culture

DISEASE(S): Breast Cancer

SUBMITTER: Alejandro Gomez-Auli

LAB HEAD: Thomas Reinheckel

PROVIDER: PXD015209 | Pride | 2021-09-08

REPOSITORIES: Pride

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	AGA08.mzML	Mzml
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Publications

The secreted inhibitor of invasive cell growth CREG1 is negatively regulated by cathepsin proteases.

Gomez-Auli Alejandro A Hillebrand Larissa Elisabeth LE Christen Daniel D Günther Sira Carolin SC Biniossek Martin Lothar ML Peters Christoph C Schilling Oliver O Reinheckel Thomas T

Cellular and molecular life sciences : CMLS 20200508 2

Previous clinical and experimental evidence strongly supports a breast cancer-promoting function of the lysosomal protease cathepsin B. However, the cathepsin B-dependent molecular pathways are not completely understood. Here, we studied the cathepsin-mediated secretome changes in the context of the MMTV-PyMT breast cancer mouse model. Employing the cell-conditioned media from tumor-macrophage co-cultures, as well as tumor interstitial fluid obtained by a novel strategy from PyMT mice with diffe ...[more]

PMID: 32385587

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The papain-like cysteine proteinases NbCysP6 and NbCysP7 are highly processive enzymes with substrate specificities complementary to Nicotiana benthamiana cathepsin B

Project description:The tobacco-related plant Nicotiana benthamiana is gaining interest as a versatile host for the production of monoclonal antibodies and other protein therapeutics. However, the susceptibility of plant-derived recombinant proteins to endogenous proteolytic enzymes limits their use as biopharmaceuticals. We have now identified two previously uncharacterized N. benthamiana proteases with high antibody-degrading activity, the papain-like cysteine proteinases NbCysP6 and NbCysP7. Both enzymes are capable of hydrolysing a wide range of synthetic substrates, although only NbCysP6 tolerates basic amino acids in its specificity-determining S2 subsite. The overlapping substrate specificities of NbCysP6 and NbCysP7 are also documented by the closely related properties of their other subsites as deduced from the action of the enzymes on proteome-derived peptide libraries. Notable differences were observed to the substrate preferences of N. benthamiana cathepsin B, another antibody-degrading papain-like cysteine proteinase. The complementary activities of NbCysP6, NbCysP7 and N. benthamiana cathepsin B indicate synergistic roles of these proteases in the turnover of recombinant and endogenous proteins in planta, thus representing a paradigm for the shaping of plant proteomes by the combined action of papain-like cysteine proteinases.

2021-12-01 | PXD005542 | Pride

Effect of Cathepsin L exposure on endothelial cell transcriptomics

Project description:Cathepsin L is a lysosomal protease that is secreted by several cancer cells. Cathepsin L upregulation has been widely associated with poor clinical outcome and increased metastatic incidence. However, whether Cathepsin L participates in tumor angiogenesis remains less studied. Our study showed a significant activation of angiogenic capacity of endothelial cells in presence of purified or tumor derived Cathepsin L. In addition, Cathepsin L exposure led to a significant increase in the proliferative capacity of endothelial cells. While the ability of Cathepsin L to promote endothelial cell sprouting, migration, invasion and tube formation can be attributed to its proteolytic effects on extracellular matrix, how it promotes endothelial cell proliferation remains obscure. The objective of this study was to test if Cathepsin L exposure can activate signaling cascades and gene expression leading to proliferation of endothelial cells.

2016-06-20 | GSE75744 | GEO

Potent anti-SARS-CoV-2 activity by the natural product gallinamide A and analogues via inhibition of cathepsin L

Project description:The emergence of SARS-CoV-2 in late 2019, and the subsequent COVID-19 pandemic, has led to substantial mortality together with mass global disruption. There is an urgent need for novel antiviral drugs for therapeutic or prophylactic application. Cathepsin L is a key host cysteine protease utilized by coronaviruses for cell entry and is recognized as a promising drug target. The marine natural product, gallinamide A and several synthetic analogues, were identified as potent inhibitors of cathepsin L activity with IC50 values in the picomolar range. Lead molecules possessed selectivity over cathepsin B and other related human cathepsin proteases and did not exhibit inhibitory activity against viral proteases Mpro and PLpro. We demonstrate that gallinamide A directly interacts with cathepsin L in cells, and together with two lead analogues potently inhibits SARS-CoV-2 infection in vitro, with EC50 values in the nanomolar range. However, in an in vivo mouse model of infection, gallinamide A did not reduce viral load in the lung tissue, possibly due to compensatory viral entry mechanisms. In support of this, in TMPRSS2-overexpressing cells gallinamide A had reduced anti-viral activity, but when combined with a TMPRSS2 inhibitor synergistically improved inhibition of viral entry. The data highlights the potential of cathepsin L as a COVID-19 antiviral drug target, and the likely necessity to inhibit multiple routes of viral entry routes to achieve therapeutic efficacy.

2022-02-17 | PXD027300 | Pride

Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

Project description:Lysosomal cathepsins regulate an exquisite range of biological functions, and their deregulation is associated with inflammatory, metabolic and degenerative disease in humans. Here, we identified a key cell-intrinsic role for cathepsin B as a negative feedback regulator of lysosomal biogenesis and autophagy. Mice and macrophages lacking cathepsin B activity had increased resistance to the cytosolic bacterial pathogen Francisella novicida. Genetic deletion or pharmacological inhibition of cathepsin B downregulated mTOR activity and prevented cleavage of the lysosomal calcium channel TRPML1. These events drove transcription of lysosomal and autophagy genes via the transcription factor TFEB, which increased lysosomal biogenesis and activation of autophagy-initiation kinase ULK1 for clearance of the bacteria. Our results identified a fundamental biological function of cathepsin B in providing a checkpoint for homeostatic maintenance of lysosome population and basic recycling functions in the cell. We used microarrays to explore the gene expression profiles differentially expressed in bone marrow-derived macrophages (BMDM) isolated from cathepsin B-/- and wild-type mice.

2016-08-04 | E-GEOD-79508 | biostudies-arrayexpress

Cathepsin B Promotes Aβ Proteotoxicity by Modulating Aging Regulating Mechanisms

Project description:While the activities of certain proteases promote proteostasis and prevent neurodegeneration-associated phenotypes, the protease cathepsin B (CTSB) enhances proteotoxicity in Alzheimer’s disease (AD) model mice, and its levels are elevated in brains of AD patients. How CTSB exacerbates the toxicity of the AD-causing Amyloid β (Aβ), is controversial. Using an activity-based probe, aging-altering interventions and the nematode C. elegans we discovered that the CTSB CPR-6 promotes Aβ proteotoxicity but mitigates the toxicity of polyQ stretches. While the knockdown of cpr-6 does not affect lifespan, it alleviates Aβ toxicity by reducing the expression of swsn-3 and elevating the level of the protein SMK-1, both involved in the regulation of aging. These observations unveil a novel mechanism by which CTSB aggravates Aβ–mediated toxicity, indicate that it plays opposing roles in the face of distinct proteotoxic insults and highlight the importance of tailoring specific remedies for distinct neurodegenerative disorders.

2024-09-03 | PXD045565 | Pride

MSP-MS of Cathepsin L and Cathepsin V pH 5.5

Project description:MSP-MS of Cathepsin L and Cathepsin V pH 5.5 at 37C

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Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection

2016-08-04 | GSE79508 | GEO

MSP-MS of Cathepsin B and Cathepsin K pH 4.6 pH 7.2

Project description:MSP-MS of Cathepsin B and Cathepsin K pH 4.6 pH 7.2

2022-02-28 | MSV000088932 | MassIVE

Effect of cathepsin inhibitors in signals associated with Th1 and Th2 mediators by Dendritic Cells

Project description:Cathepsin inhibitors have been associated to induce changes in Th1/Th2 polarization; cathepsin B inhibitor CA074 has been reported to induce a Th1 polarization, whereas cathepsin L inhibitor CLIK148 has been reported to induce a Th2 polarization. In this study, we pre-treated bone marrow-derived dendritic cells (BMDC) with CA074Me or CLIK148, followed by stimulation with a known pro-Th1 inducer (CpG) and a known pro-Th2 inducer (TNF-alpha) and analyzed by microarrays the expression of genes acting as pro-Th1 or pro-Th2 mediators.

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TH2 cytokines promote tumor progression via regulating cathepsin secretion in tumor-associated macrophages

Project description:Tumor-associated macrophages (TAMs) have emerged as prominent cells within the tumor microenvironment playing critical roles in extracellular matrix remodeling, tumor cell proliferation and invasion, angiogenesis, and metastasis. Cathepsin proteases, produced by tumor cells and TAMs, have been demonstrated to mediate these processes, but it still remains unclear how these typically lysosomal enzymes are capable of executing their functions in the extracellular space. Here we identify a novel interaction between STAT6 and STAT3 that potently upregulates cathepsin secretion in macrophages in response to TH2 cytokine stimulation. Systematic gene expression analyses reveal that the TH2 cytokine IL-4 synergizes with IL-6 or IL-10 to activate the IRE1α/ XBP1 axis of the unfolded protein response. Pharmacological inhibition of the IRE1α axis blunts cathepsin secretion in macrophages and blocks macrophage-mediated tumor cell invasion. Finally, we show that genetic ablation of either STAT6 or STAT3 signaling impairs tumor development and invasion. Thus, these findings demonstrate that TH2 cytokine-mediated STAT6 and STAT3 activation in macrophages promotes a professional secretory phenotype capable of enhancing tumor cell invasion in a cathepsin-dependent manner.

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