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Communications Biology Oct 2023Lung cancer, a major contributor to cancer-related fatalities worldwide, involves a complex pathogenesis. Cathepsins, lysosomal cysteine proteases, play roles in various...
Lung cancer, a major contributor to cancer-related fatalities worldwide, involves a complex pathogenesis. Cathepsins, lysosomal cysteine proteases, play roles in various physiological and pathological processes, including tumorigenesis. Observational studies have suggested an association between cathepsins and lung cancer. However, the causal link between the cathepsin family and lung cancer remains undetermined. This study employed Mendelian randomization analyses to investigate this causal association. The univariable Mendelian randomization analysis results indicate that elevated cathepsin H levels increase the overall risk of lung cancer, adenocarcinoma, and lung cancer among smokers. Conversely, reverse Mendelian randomization analyses suggest that squamous carcinoma may lead to increased cathepsin B levels. A multivariable analysis using nine cathepsins as covariates reveals that elevated cathepsin H levels lead to an increased overall risk of lung cancer, adenocarcinoma, and lung cancer in smokers. In conclusion, cathepsin H may serve as a marker for lung cancer, potentially inspiring directions in lung cancer diagnosis and treatment.
Topics: Humans; Cathepsin H; Lung Neoplasms; Mendelian Randomization Analysis; Cathepsin L; Adenocarcinoma
PubMed: 37805623
DOI: 10.1038/s42003-023-05408-7 -
Cancer Cell Sep 2022Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop...
Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.
Topics: Animals; Carcinoma, Squamous Cell; Cell Differentiation; Cisplatin; Humans; Mice; Urinary Bladder Neoplasms
PubMed: 36099882
DOI: 10.1016/j.ccell.2022.08.010 -
Biochimica Et Biophysica Acta. Proteins... Sep 2020Microglia, the resident mononuclear phagocyte population in the brain, have long been implicated in the pathology of neurodegenerative age-associated disorders. However,... (Review)
Review
Microglia, the resident mononuclear phagocyte population in the brain, have long been implicated in the pathology of neurodegenerative age-associated disorders. However, activated microglia have now been identified as homeostatic keepers in the brain, because they are involved in the initiation and resolution of neuropathology. The complex roles of activated microglia appear to be linked to change from inflammatory and neurotoxic to anti-inflammatory and neuroprotective phenotypes. Increased expression and secretion of various cathepsins support roles of activated microglia in chronic neuroinflammation, the neurotoxic M1-like polarization and neuronal death. Moreover, changes in expression and localization of microglial cathepsin B play a critical role in the acceleration of the brain aging. Beyond the role as brain-resident macrophages, many lines of evidence have shown that microglia have essential roles in the maturation and maintenance of neuronal circuits in the developing and adult brain. Cathepsin S secreted from microglia induces the diurnal variation of spine density of cortical neurons though proteolytic modification of peri-synaptic extracellular matrix molecules. In this review, I highlight the emerging roles of cathepsins that support the roles of microglia in both normal healthy and pathological brains. In addition, I discuss cathepsin inhibitors as potential therapeutic targets for brain disorders.
Topics: Animals; Brain; Cathepsin B; Cathepsin H; Cathepsins; Chronic Pain; Humans; Inflammation; Microglia; NLR Family, Pyrin Domain-Containing 3 Protein; Neurodegenerative Diseases; Neurons; Phenotype
PubMed: 32526473
DOI: 10.1016/j.bbapap.2020.140465 -
The Biochemical Journal Nov 1980Cathepsin H was purified from human liver by a method involving autolysis and acetone fractionation, and chromatography on DEAE-cellulose, Ultrogel AcA 54,...
Cathepsin H was purified from human liver by a method involving autolysis and acetone fractionation, and chromatography on DEAE-cellulose, Ultrogel AcA 54, hydroxyapatite and concanavalin A-Sepharose. The procedure allowed for the simultaneous isolation of cathepsin B and cathepsin D. Cathepsin H was shown to consist of a single polypeptide chain of 28 000 mol.wt., and affinity for concanavalin A-Sepharose indicated that it was a glycoprotein. The enzyme existed in multiple isoelectric forms, the two major forms having pI values of 6.0 and 6.4; it hydrolysed azocasein (pH optimum 5.5), benzoylarginine 2-naphthylamide (Ba-Arg-NNap), leucyl 2-naphthylamide (Arg-NNap), (pH optimum 6.8). Arg-NNap and Arg-NMec, unlike Bz-Arg-NNap-, were not hydrolysed by human cathepsin B. Cathepsin H was similar to cathepsin B in being irreversibly inactivated by exposure to alkaline pH. Sensitivity to chemical inhibitors by 1 microM-leupeptin, which gave essentially complete inhibition of the other lysosomal cysteine proteinases, cathepsins B and L.
Topics: Cathepsins; Chemical Phenomena; Chemistry; Chromatography, DEAE-Cellulose; Chromatography, Gel; Humans; Isoenzymes; Liver; Methods; Substrate Specificity; alpha-Macroglobulins
PubMed: 6165352
DOI: 10.1042/bj1910487 -
PloS One 2018Cathepsin H is a member of the papain superfamily of lysosomal cysteine proteases. It is the only known aminopeptidase in the family and is reported to be involved in...
Cathepsin H is a member of the papain superfamily of lysosomal cysteine proteases. It is the only known aminopeptidase in the family and is reported to be involved in cancer and other major diseases. Like many other proteases, it is synthesized as an inactive proenzyme. Although the crystal structure of mature porcine cathepsin H revealed the binding of the mini-chain and provided structural basis for the aminopeptidase activity, detailed structural and functional information on the inhibition and activation of procathepsin H has been elusive. Here we present the crystal structures of human procathepsin H at 2.00 Å and 1.66 Å resolution. These structures allow us to explore in detail the molecular basis for the inhibition of the mature domain by the prodomain. Comparison with cathepsin H structure reveals how mini-chain reorients upon activation. We further demonstrate that procathepsin H is not auto-activated but can be trans-activated by cathepsin L.
Topics: Cathepsin H; Cathepsin L; Crystallization; Enzyme Precursors; HEK293 Cells; Humans; Molecular Dynamics Simulation; Protein Conformation; Recombinant Proteins
PubMed: 30044821
DOI: 10.1371/journal.pone.0200374 -
Cancer Cell Sep 2022In this issue of Cancer Cell, Wang et al. reveal that chemoresistant muscle-invasive bladder cancer is associated with partial squamous differentiation. Targeting of...
In this issue of Cancer Cell, Wang et al. reveal that chemoresistant muscle-invasive bladder cancer is associated with partial squamous differentiation. Targeting of Cathepsin H overcomes this chemotherapy-induced semi-squamatization and promotes terminal squamous differentiation and tumor suppression.
Topics: Carcinoma, Squamous Cell; Drug Resistance, Neoplasm; Humans; Urinary Bladder Neoplasms
PubMed: 36099886
DOI: 10.1016/j.ccell.2022.08.020 -
Cellular and Molecular Gastroenterology... 2023Improving clinical management of early stage colorectal cancers (T1CRCs) requires a better understanding of their underlying biology. Accumulating evidence shows that...
BACKGROUND & AIMS
Improving clinical management of early stage colorectal cancers (T1CRCs) requires a better understanding of their underlying biology. Accumulating evidence shows that cancer-associated fibroblasts (CAFs) are important determinants of tumor progression in advanced colorectal cancer (CRC), but their role in the initial stages of CRC tumorigenesis is unknown. Therefore, we investigated the contribution of T1CAFs to early CRC progression.
METHODS
Primary T1CAFs and patient-matched normal fibroblasts (NFs) were isolated from endoscopic biopsy specimens of histologically confirmed T1CRCs and normal mucosa, respectively. The impact of T1CAFs and NFs on tumor behavior was studied using 3-dimensional co-culture systems with primary T1CRC organoids and extracellular matrix (ECM) remodeling assays. Whole-transcriptome sequencing and gene silencing were used to pinpoint mediators of T1CAF functions.
RESULTS
In 3-dimensional multicellular cultures, matrix invasion of T1CRC organoids was induced by T1CAFs, but not by matched NFs. Enhanced T1CRC invasion was accompanied by T1CAF-induced ECM remodeling and up-regulation of CD44 in epithelial cells. RNA sequencing of 10 NF-T1CAF pairs revealed 404 differentially expressed genes, with significant enrichment for ECM-related pathways in T1CAFs. Cathepsin H, a cysteine-type protease that was specifically up-regulated in T1CAFs but not in fibroblasts from premalignant lesions or advanced CRCs, was identified as a key factor driving matrix remodeling by T1CAFs. Finally, we showed high abundance of cathepsin H-expressing T1CAFs at the invasive front of primary T1CRC sections.
CONCLUSIONS
Already in the earliest stage of CRC, cancer cell invasion is promoted by CAFs via direct interactions with epithelial cancer cells and stage-specific, cathepsin H-dependent ECM remodeling. RNA sequencing data of the 10 NF-T1CAF pairs can be found under GEO accession number GSE200660.
Topics: Humans; Cancer-Associated Fibroblasts; Cathepsin H; Neoplasm Invasiveness; Fibroblasts; Colorectal Neoplasms
PubMed: 37085135
DOI: 10.1016/j.jcmgh.2023.04.004 -
The European Respiratory Journal Jun 2008Pulmonary alveolar proteinosis (PAP) is a group of rare diseases with disturbed homeostasis of alveolar surfactant. While 90% of the primary adult forms are caused by...
Pulmonary alveolar proteinosis (PAP) is a group of rare diseases with disturbed homeostasis of alveolar surfactant. While 90% of the primary adult forms are caused by granulocyte-macrophage colony-stimulating factor autoantibodies, the underlying cause of the juvenile form remains unknown. In order to distinguish primary from secondary effects in the pathogenesis of these two forms, the present authors studied the surfactant protein processing proteases napsin A and cathepsin H. In total, 16 controls, 20 patients with juvenile PAP and 13 adults with idiopathic PAP were enrolled. Amounts and activities of the proteases in the bronchoalveolar lavage fluid (BALF) were determined by immunoblotting and specific substrate cleavage. Both proteases were present and active in BALF from controls and increased in juvenile and adult PAP patients. The amount of active cathepsin H in relation to total cathepsin H was increased in PAP patients compared with controls. Cystatin C, the physiological inhibitor of cathepsin H in the alveolar space, was not increased to the same degree as cathepsin H, resulting in an imbalance of inhibitor to protease in the alveolar space. A general defect in napsin A or cathepsin H expression or activity was not the specific cause for abnormal surfactant accumulation in juvenile pulmonary alveolar proteinosis.
Topics: Adult; Aspartic Acid Endopeptidases; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cathepsin H; Cathepsins; Child, Preschool; Cystatin C; Cystatins; Cysteine Endopeptidases; Humans; Infant; Pulmonary Alveolar Proteinosis
PubMed: 18216060
DOI: 10.1183/09031936.00081207 -
Current Opinion in Neurobiology Oct 2013Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep... (Review)
Review
Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. Narcolepsy is caused by the loss of hypocretin (orexin)-producing neurons in the lateral hypothalamus. Evidence, such as a strong association with HLA DQB1*06:02, strongly suggests an autoimmune basis targeting hypocretin neurons. Genome-wide association studies have strengthened the association between narcolepsy and immune system gene polymorphisms, including the identification of polymorphisms in the T cell receptor alpha locus, TNFSF4 (also called OX40L), Cathepsin H (CTSH) the purinergic receptor P2RY11, and the DNA methyltransferase DNMT1. Recently, attention has been raised regarding a spike in cases of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Europe. How the immune system may be involved in disease initiation and/or progression remains a challenge to researchers. Potential immunological pathways that could lead to the specific elimination of hypocretin producing neurons include molecular mimicry or bystander activation, and are likely a combination of genetic and environmental factors, such as upper airway infections.
Topics: Animals; Autoimmune Diseases; Genetic Predisposition to Disease; HLA-DQ beta-Chains; Humans; Influenza A Virus, H1N1 Subtype; Molecular Mimicry; Narcolepsy
PubMed: 23725858
DOI: 10.1016/j.conb.2013.04.013 -
Genes Oct 2021Emerging evidence suggests that several of the lysosomal cathepsin proteases are genetically associated with type 1 diabetes (T1D) and participate in immune-mediated...
Emerging evidence suggests that several of the lysosomal cathepsin proteases are genetically associated with type 1 diabetes (T1D) and participate in immune-mediated destruction of the pancreatic β cells. We previously reported that the T1D candidate gene cathepsin H is downregulated by pro-inflammatory cytokines in human pancreatic islets and regulates β-cell function, apoptosis, and disease progression in children with new-onset T1D. In the present study, the objective was to investigate the expression patterns of all 15 known cathepsins in β-cell model systems and examine their role in the regulation of cytokine-induced apoptosis. Real-time qPCR screening of the cathepsins in human islets, 1.1B4 and INS-1E β-cell models identified several cathepsins that were expressed and regulated by pro-inflammatory cytokines. Using small interfering RNAs to knock down (KD) the cytokine-regulated cathepsins, we identified an anti-apoptotic function of cathepsin C as KD increased cytokine-induced apoptosis. KD of cathepsin C correlated with increased phosphorylation of JNK and p38 mitogen-activated protein kinases, and elevated chemokine CXCL10/IP-10 expression. This study suggests that cathepsin C is a modulator of β-cell survival, and that immune modulation of cathepsin expression in islets may contribute to immune-mediated β-cell destruction in T1D.
Topics: Animals; Apoptosis; Cathepsin C; Cells, Cultured; Cytokines; Diabetes Mellitus, Type 1; Humans; Insulin-Secreting Cells; Islets of Langerhans; Models, Biological; Rats
PubMed: 34828301
DOI: 10.3390/genes12111694