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Cancer Cell Oct 2022How glucose metabolism remodels pro-tumor functions of tumor-associated macrophages (TAMs) needs further investigation. Here we show that M2-like TAMs bear the highest...
How glucose metabolism remodels pro-tumor functions of tumor-associated macrophages (TAMs) needs further investigation. Here we show that M2-like TAMs bear the highest individual capacity to take up intratumoral glucose. Their increased glucose uptake fuels hexosamine biosynthetic pathway-dependent O-GlcNAcylation to promote cancer metastasis and chemoresistance. Glucose metabolism promotes O-GlcNAcylation of the lysosome-encapsulated protease Cathepsin B at serine 210, mediated by lysosome-localized O-GlcNAc transferase (OGT), elevating mature Cathepsin B in macrophages and its secretion in the tumor microenvironment (TME). Loss of OGT in macrophages reduces O-GlcNAcylation and mature Cathepsin B in the TME and disrupts cancer metastasis and chemoresistance. Human TAMs with high OGT are positively correlated with Cathepsin B expression, and both levels predict chemotherapy response and prognosis of individuals with cancer. Our study reports the biological and potential clinical significance of glucose metabolism in tumor-promoting TAMs and reveals insights into the underlying mechanisms.
Topics: Cathepsin B; Drug Resistance, Neoplasm; Glucose; Hexosamines; Humans; Lysosomes; N-Acetylglucosaminyltransferases; Neoplasms; Serine; Tumor Microenvironment; Tumor-Associated Macrophages
PubMed: 36084651
DOI: 10.1016/j.ccell.2022.08.012 -
Cancer Letters May 2019Clinical, biochemical and molecular biology studies have identified lysosome-encapsulated cellular proteases as critical risk factors for cancer progression. Cathepsins... (Review)
Review
Clinical, biochemical and molecular biology studies have identified lysosome-encapsulated cellular proteases as critical risk factors for cancer progression. Cathepsins represent a group of such proteases aimed at maintenance of cellular homeostasis. Nevertheless, recent reports suggest that Cathepsin B executes other cellular programs such as controlling tumor growth, migration, invasion, angiogenesis, and metastases development. In fact, elevated levels of Cathepsins are found under different pathological conditions including inflammation, infection, neurodegenerative disease, and cancer. Furthermore, the discovery of Cathepsin B secretion and function as an extracellular matrix protein has broadened our appreciation for the impact of Cathepsin B on cancer progression. Underneath a façade of an intracellular protease with limited therapeutic potential hides a central role of cathepsins in extracellular functions. Moreover, this role is incredibly diverse from one condition to the next - from driving caspase-dependent apoptosis to facilitating tumor neovascularization and metastasis. Here we discuss the role of Cathepsin B in the oncogenic process and perspective the use of Cathepsin B for diagnostic and therapeutic applications.
Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Biomarkers, Tumor; Cathepsin B; Cell Movement; Humans; Neoplasm Invasiveness; Neoplasms; Protease Inhibitors; RNAi Therapeutics; Signal Transduction
PubMed: 30796968
DOI: 10.1016/j.canlet.2019.02.035 -
Journal For Immunotherapy of Cancer Oct 2022The loss of tumor antigens and depletion of CD8 T cells caused by the PD-1/PD-L1 pathway are important factors for tumor immune escape. In recent years, there has been...
BACKGROUND
The loss of tumor antigens and depletion of CD8 T cells caused by the PD-1/PD-L1 pathway are important factors for tumor immune escape. In recent years, there has been increasing research on traditional Chinese medicine in tumor treatment. Cycloastragenol (CAG), an effective active molecule in , has been found to have antiviral, anti-aging, anti-inflammatory, and other functions. However, its antitumor effect and mechanism are not clear.
METHODS
The antitumor effect of CAG was investigated in MC38 and CT26 mouse transplanted tumor models. The antitumor effect of CAG was further analyzed via single-cell multiomics sequencing. Target responsive accessibility profiling technology was used to find the target protein of CAG. Subsequently, the antitumor mechanism of CAG was explored using confocal microscopy, coimmunoprecipitation and transfection of mutant plasmids. Finally, the combined antitumor effect of CAG and PD-1 antibodies in mice or organoids were investigated.
RESULTS
We found that CAG effectively inhibited tumor growth in vivo. Our single-cell multiomics atlas demonstrated that CAG promoted the presentation of tumor cell-surface antigens and was characterized by the enhanced killing function of CD8 T cells. Mechanistically, CAG bound to its target protein cathepsin B, which then inhibited the lysosomal degradation of major histocompatibility complex I (MHC-I) and promoted the aggregation of MHC-I to the cell membrane, boosting the presentation of the tumor antigen. Meanwhile, the combination of CAG with PD-1 antibody effectively enhanced the tumor killing ability of CD8 T cells in xenograft mice and colorectal cancer organoids.
CONCLUSION
Our data reported for the first time that cathepsin B downregulation confers antitumor immunity and explicates the antitumor mechanism of natural product CAG.
Topics: Humans; Mice; Animals; CD8-Positive T-Lymphocytes; Programmed Cell Death 1 Receptor; Cathepsin B; Mice, Inbred C57BL; Cell Line, Tumor; Antibodies; Antigens, Neoplasm; Proteins; Major Histocompatibility Complex
PubMed: 36307151
DOI: 10.1136/jitc-2022-004874 -
Cell Metabolism Aug 2016Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB)... (Randomized Controlled Trial)
Randomized Controlled Trial
Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition.
Topics: Adult; Affect; Aging; Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Cathepsin B; Cognition; Doublecortin Domain Proteins; Doublecortin Protein; Exercise Test; Female; Hippocampus; Humans; Macaca mulatta; Male; Memory; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins; Motor Activity; Neurogenesis; Neurons; Neuropeptides; Physical Conditioning, Animal; Reproducibility of Results; Running; Sedentary Behavior; Young Adult
PubMed: 27345423
DOI: 10.1016/j.cmet.2016.05.025 -
International Journal of Molecular... Oct 2023Papain-like cysteine proteases are composed of 11 human cysteine cathepsins, originally located in the lysosomes. They exhibit broad specificity and act as... (Review)
Review
Papain-like cysteine proteases are composed of 11 human cysteine cathepsins, originally located in the lysosomes. They exhibit broad specificity and act as endopeptidases and/or exopeptidases. Among them, only cathepsins B, H, C, and X/Z exhibit exopeptidase activity. Recently, cysteine cathepsins have been found to be present outside the lysosomes and often participate in various pathological processes. Hence, they have been considered key signalling molecules. Their potentially hazardous proteolytic activities are tightly regulated. This review aims to discuss recent advances in understanding the structural aspects of these four cathepsins, mechanisms of their zymogen activation, regulation of their activities, and functional aspects of these enzymes in neurodegeneration and cancer. Neurodegenerative effects have been evaluated, particularly in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and neuropsychiatric disorders. Cysteine cathepsins also participate in tumour progression and metastasis through the overexpression and secretion of proteases, which trigger extracellular matrix degradation. To our knowledge, this is the first review to provide an in-depth analysis regarding the roles of cysteine cathepsins B, H, C, and X in neurodegenerative diseases and cancer. Further advances in understanding the functions of cysteine cathepsins in these conditions will result in the development of novel, targeted therapeutic strategies.
Topics: Humans; Cysteine Proteases; Neurodegenerative Diseases; Cysteine; Cathepsin B; Neoplasms; Lysosomes
PubMed: 37958596
DOI: 10.3390/ijms242115613 -
Cell Death & Disease Apr 2023Cathepsin B (CatB), a cysteine protease, is primarily localized within subcellular endosomal and lysosomal compartments. It is involved in the turnover of intracellular... (Review)
Review
Cathepsin B (CatB), a cysteine protease, is primarily localized within subcellular endosomal and lysosomal compartments. It is involved in the turnover of intracellular and extracellular proteins. Interest is growing in CatB due to its diverse roles in physiological and pathological processes. In functional defective tissues, programmed cell death (PCD) is one of the regulable fundamental mechanisms mediated by CatB, including apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagic cell death. However, CatB-mediated PCD is responsible for disease progression under pathological conditions. In this review, we provide an overview of the critical roles and regulatory pathways of CatB in different types of PCD, and discuss the possibility of CatB as an attractive target in multiple diseases. We also summarize current gaps in the understanding of the involvement of CatB in PCD to highlight future avenues for research.
Topics: Cathepsin B; Apoptosis; Pyroptosis; Lysosomes
PubMed: 37031185
DOI: 10.1038/s41419-023-05786-0 -
Theranostics 2017Cysteine cathepsins are a group of proteases involved in many physiological and pathological processes. Yet, the selective detection and inhibition of individual...
Cysteine cathepsins are a group of proteases involved in many physiological and pathological processes. Yet, the selective detection and inhibition of individual cathepsins is still challenging. This editorial is discussing the context of a recent work introducing a designed ankyrin repeat protein (DARPin) as novel approach for selective targeting of the protease cathepsin B.
Topics: Cathepsin B; Cathepsins; Cysteine; Humans; Neoplasms
PubMed: 28824729
DOI: 10.7150/thno.21603 -
International Journal of Molecular... Jan 2023Enniatin B (ENN B) and Beauvericin (BEA) are cyclohexadepsipeptides that can be isolated from and , respectively. Both compounds are cytotoxic and ionophoric. In the...
Enniatin B (ENN B) and Beauvericin (BEA) are cyclohexadepsipeptides that can be isolated from and , respectively. Both compounds are cytotoxic and ionophoric. In the present study, the mechanism of cell death induced by these compounds was investigated. Epidermal carcinoma-derived cell line KB-3-1 cells were treated with different concentrations of these compounds. The extracellular secretion of cathepsin B increased in a concentration-dependent manner, and the lysosomal staining by lysotracker red was reduced upon the treatment with any of the compounds. However, the extracellular secretion of cathepsin L and cathepsin D were not affected. Inhibition of cathepsin B with specific inhibitor CA074 significantly reduced the cytotoxic effect of both compounds, while inhibition of cathepsin D or cathepsin L did not influence the cytotoxic activities of both compounds. In vitro labelling of lysosomal cysteine cathepsins with Ethyl (2S, 3S)-epoxysuccinate-Leu-Tyr-Acp-Lys (Biotin)-NH2 (DCG04) was not affected in case of cathepsin L upon the treatment with both compounds, while it was significantly reduced in case of cathepsin B. In conclusion, ENN B and BEA increase lysosomal Ph, which inhibits delivery of cathepsin B from Golgi to lysosomes, thereby inducing cathepsin B release in cytosol, which activates caspases and hence the apoptotic pathway.
Topics: Cathepsin B; Cathepsin D; Cathepsin L; Cell Death; Apoptosis; Lysosomes
PubMed: 36768354
DOI: 10.3390/ijms24032030 -
Pharmacological Reviews Jul 2022Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and... (Review)
Review
Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion of the gene resulted in significant improvements in behavioral deficits, neuropathology, and/or biomarkers in traumatic brain injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer's disease (AD), and periodontitis AD models as shown in 12 studies. One study found beneficial effects for double and cathepsin S KO mice in a multiple sclerosis model. Transgenic AD models using amyloid precursor protein (APP) mimicking common sporadic AD in three studies showed that KO improved memory, neuropathology, and biomarkers; two studies used APP representing rare familial AD and found no KO effect, and two studies used highly engineered APP constructs and reported slight increases in a biomarker. In clinical studies, all reports found that CTSB enzyme was upregulated in diverse neurologic disorders, including AD in which elevated CTSB was positively correlated with cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational drug target and for CTSB inhibitors as therapeutic candidates for a wide range of neurologic disorders. SIGNIFICANCE STATEMENT: This review provides a comprehensive compilation of the extensive data on the effects of deleting the cathepsin B () gene in neurological and aging mouse models of brain disorders. Mice lacking the gene display improved neurobehavioral deficits, reduced neuropathology, and amelioration of neuronal cell death and inflammatory biomarkers. The significance of the compelling CTSB evidence is that the data consilience validates CTSB as a drug target for discovery of CTSB inhibitors as potential therapeutics for treating numerous neurological diseases.
Topics: Alzheimer Disease; Animals; Cathepsin B; Disease Models, Animal; Gene Knockout Techniques; Humans; Mice; Mice, Knockout; Mice, Transgenic
PubMed: 35710131
DOI: 10.1124/pharmrev.121.000527 -
Biomolecules Dec 2020Caffeic acid (CA) and its derivatives caffeic acid phenethyl ester (CAPE) and chlorogenic acid (CGA) are phenolic compounds of plant origin with a wide range of...
Caffeic acid (CA) and its derivatives caffeic acid phenethyl ester (CAPE) and chlorogenic acid (CGA) are phenolic compounds of plant origin with a wide range of biological activities. Here, we identify and characterize their inhibitory properties against human cathepsins B and L, potent, ubiquitously expressed cysteine peptidases involved in protein turnover and homeostasis, as well as pathological conditions, such as cancer. We show that CAPE and CGA inhibit both peptidases, while CA shows a preference for cathepsin B, resulting in the strongest inhibition among these combinations. All compounds are linear (complete) inhibitors acting via mixed or catalytic mechanisms. Cathepsin B is more strongly inhibited at pH 7.4 than at 5.5, and CA inhibits its endopeptidase activity preferentially over its peptidyl-dipeptidase activity. Altogether, the results identify the CA scaffold as a promising candidate for the development of cathepsin B inhibitors, specifically targeting its endopeptidase activity associated with pathological proteolysis of extracellular substrates.
Topics: Caffeic Acids; Cathepsin B; Cathepsin L; Chlorogenic Acid; Drug Discovery; Enzyme Inhibitors; Humans; Phenylethyl Alcohol; Proteolysis
PubMed: 33383850
DOI: 10.3390/biom11010031