scholarly journals Potential Role of Cathepsin K in Regulation of Micro Tumor Environment, Onset and Progression of Cancers in Human- A Review

2020 ◽  
Author(s):  
Ruwini Cooray ◽  
Hasanka Madubashetha ◽  
Sachith Wickramasinghe ◽  
Lakshan Warnakula ◽  
Nimali De Silva
Keyword(s):  
Enzymatic Activity ◽  
Proteolytic Enzymes ◽  
Cathepsin K ◽  
Breast Cancers ◽  
Healthy Human ◽  
Adverse Health Effects ◽  
Cysteine Cathepsin ◽  
Tumor Environment ◽  
Prostate Cancers ◽  
Immunohistochemical Studies

The effect of proteolytic enzymes including Cathepsin K, a cysteine cathepsin, in onset and progression of cancers in human has been research intensive. Cathepsin K involves in many aspects and stages of cancers including apoptosis, cell proliferation, cancer immunology, inflammatory cell recruitment to tumors and aiding in the process of mobilization of normal healthy cells from their tissue compartments assisting in metastasis and angiogenesis. The objective of this review is to collect together and summarize and analyze the biochemical and physiological pathways of how cathepsin K is involved in onset and progression of cancers with more emphasis on breast and prostate cancers and cathepsin K regulated mechanisms underlying metastasis of such cancers to bones. Information for the review was gathered through published literature from global databases such as Google Scholar, PUBMED and NCBI on different studies on physiological interactions between enzymatic activity of cathepsin K with cancers and metastasis to bones. Analysis of published studies reveal that immunohistochemical studies of breast cancer cells indicate that they overexpress cathepsin K resulting in induction of aberrant mechanisms of cell signaling in breast cancers, creating a higher tendency for their metastasis to bones. Immunohistochemical, immunoprecipitation and fluorgenic assays of several studies done on the association of the same enzymatic activity on prostate cancers shows elevated levels of cathepsin K. Lesions derived from prostate cancer cell masses were observed to undergo increased bone formation and resorption levels. Such resorption levels cause secretion of biological factors promoting tumor expansion. In addition, studies indicate that Cathepsin K was observed to be a key component promoting higher bone resorption levels in patients suffering from cancer. Authors suggest that, to completely understand the association of cathepsin K on cancerous cells and their mechanism in metastasis, distributary patterns of cathepsin K in healthy human tissues needs to be extensively studied initially. It is also suggested that metastasis of breast and prostate cancers to bone could be terminated and overcome by successful production of efficient and precise inhibitory therapeutics targeting the enzymatic activity of Cathepsin K with minimum unintended adverse health effects.

Cartilage Destruction Is Partly Induced by the Internal Proteolytic Enzymes and Apoptotic Phenomenon of Chondrocytes in Relapsing Polychondritis

2011 ◽  
Vol 38 (4) ◽  
pp. 730-737 ◽  
Author(s):  
NAOHISA OUCHI ◽  
MIWA UZUKI ◽  
AKIHISA KAMATAKI ◽  
YASUHIRO MIURA ◽  
TAKASHI SAWAI
Keyword(s):  
Proteolytic Enzymes ◽  
Relapsing Polychondritis ◽  
Cathepsin K ◽  
Cartilage Destruction ◽  
Related Factor ◽  
Apoptotic Cells ◽  
Intrinsic Factors ◽  
Immunological Disorder ◽  
Immunohistochemical Studies ◽  
Surgical Operations

Objective.We analyzed 9 cases by immunohistochemical studies in order to elucidate the mechanisms of cartilage destruction in relapsing polychondritis (RP), which often involves the external auricle and respiratory tract through immunological disorder.Methods.Cartilage tissues were obtained during surgical operations. Cell species in the granulation tissues, especially near the cartilage, were identified by cell-surface markers [CD3, CD4, CD8, CD20, CD45 (LCA), and CD68]. The proteolytic enzymes expressed in the cells in the perichondral granulation and in chondrocytes themselves were analyzed by immunohistochemical studies using anti-matrix metalloproteinase (MMP) -1, -3, -8, -9, and -13, and cathepsin D, K, L, and elastase antibodies. Apoptosis and nitric oxide (NO), an apoptosis-related factor, were also examined using ApopTag and antinitrotyrosine antibody, respectively.Results.Among cell species that infiltrated in perichondral granulation, LCA, CD68 (monocytes/macrophages), and CD4 cells were dominant in number; MMP-8, MMP-9, and elastase were expressed only in the perichondral granulation; whereas MMP-3 and cathepsin K and L were detected in both chondrocytes and granulations. Out of 9 cases examined, 6 revealed apoptotic cells in excess of 50% of chondrocytes. There was a strong correlation between the number of apoptotic cells and the number of MMP-3-positive (r = 0.83) and cathepsin K-positive cells (r = 0.92). Abundant NO-expressing cells were observed in the chondrocytes in degenerated cartilage, similar to apoptosis.Conclusion.Cartilage destruction in polychondritis is induced not only by perichondral inflammation, but also by intrinsic factors expressed in chondrocytes themselves, including certain kinds of proteolytic enzymes and apoptosis.

Genetic parkinsonisms and cancer: a systematic review and meta-analysis

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Andrea Sturchio ◽  
Alok K. Dwivedi ◽  
Joaquin A. Vizcarra ◽  
Martina Chirra ◽  
Elizabeth G. Keeling ◽  
...  
Keyword(s):  
Head And Neck ◽  
Meta Analysis ◽  
Head And Neck Cancers ◽  
Breast Cancers ◽  
Asymptomatic Carriers ◽  
Skin Cancers ◽  
Prostate Cancers ◽  
Meta Analyses ◽  
Genetic Contributions ◽  
Nonmelanoma Skin Cancers

AbstractGenes associated with parkinsonism may also be implicated in carcinogenesis, but their interplay remains unclear. We systematically reviewed studies (PubMed 1967–2019) reporting gene variants associated with both parkinsonism and cancer. Somatic variants were examined in cancer samples, whereas germline variants were examined in cancer patients with both symptomatic and asymptomatic (carriers) genetic parkinsonisms. Pooled proportions were calculated with random-effects meta-analyses. Out of 9,967 eligible articles, 60 were included. Of the 28 genetic variants associated with parkinsonism, six were also associated with cancer. In cancer samples, SNCA was predominantly associated with gastrointestinal cancers, UCHL1 with breast cancer, and PRKN with head-and-neck cancers. In asymptomatic carriers, LRRK2 was predominantly associated with gastrointestinal and prostate cancers, PRKN with prostate and genitourinary tract cancers, GBA with sarcoma, and 22q11.2 deletion with leukemia. In symptomatic genetic parkinsonism, LRRK2 was associated with nonmelanoma skin cancers and breast cancers, and PRKN with head-and-neck cancers. Cancer was more often manifested in genetic parkinsonisms compared to asymptomatic carriers. These results suggest that intraindividual genetic contributions may modify the co-occurrence of cancer and neurodegeneration.

scholarly journals Sickle Cell Anemia Mediates Carotid Artery Expansive Remodeling That Can Be Prevented by Inhibition of JNK (c-Jun N-Terminal Kinase)

2020 ◽  
Vol 40 (5) ◽  
pp. 1220-1230 ◽  
Author(s):  
Hannah Song ◽  
Philip M. Keegan ◽  
Suhaas Anbazhakan ◽  
Christian P. Rivera ◽  
Yundi Feng ◽  
...  
Keyword(s):  
Carotid Artery ◽  
Mouse Model ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Structural Damage ◽  
Proteolytic Enzymes ◽  
Arterial Compliance ◽  
Cathepsin K ◽  
Large Artery ◽  
Elastic Lamina

Objective: Sickle cell anemia (SCA) causes chronic inflammation and multiorgan damage. Less understood are the arterial complications, most evident by increased strokes among children. Proteolytic mechanisms, biomechanical consequences, and pharmaceutical inhibitory strategies were studied in a mouse model to provide a platform for mechanistic and intervention studies of large artery damage due to sickle cell disease. Approach and Results: Townes humanized transgenic mouse model of SCA was used to test the hypothesis that elastic lamina and structural damage in carotid arteries increased with age and was accelerated in mice homozygous for SCA (sickle cell anemia homozygous genotype [SS]) due to inflammatory signaling pathways activating proteolytic enzymes. Elastic lamina fragmentation observed by 1 month in SS mice compared with heterozygous littermate controls (sickle cell trait heterozygous genotype [AS]). Positive immunostaining for cathepsin K, a powerful collagenase and elastase, confirmed accelerated proteolytic activity in SS carotids. Larger cross-sectional areas were quantified by magnetic resonance angiography and increased arterial compliance in SS carotids were also measured. Inhibiting JNK (c-jun N-terminal kinase) signaling with SP600125 significantly reduced cathepsin K expression, elastin fragmentation, and carotid artery perimeters in SS mice. By 5 months of age, continued medial thinning and collagen degradation was mitigated by treatment of SS mice with JNK inhibitor. Conclusions: Arterial remodeling due to SCA is mediated by JNK signaling, cathepsin proteolytic upregulation, and degradation of elastin and collagen. Demonstration in Townes mice establishes their utility for mechanistic studies of arterial vasculopathy, related complications, and therapeutic interventions for large artery damage due to SCA.

Myoglobin content and enzymatic activity of muscle and altitude adaptation

1962 ◽  
Vol 17 (2) ◽  
pp. 301-305 ◽  
Author(s):  
Baltazar Reynafarje
Keyword(s):  
Cytochrome C ◽  
Enzymatic Activity ◽  
High Altitude ◽  
Sea Level ◽  
Human Subjects ◽  
Reduced Form ◽  
Sartorius Muscle ◽  
Healthy Human ◽  
Altitude Adaptation ◽  
Made In

Quantitative determinations of myoglobin were made in the sartorius muscle of healthy human subjects native to sea level and high altitude. The specific activities of the reduced form of diphosphopyridine nucleotide oxidase (DPNH-oxidase), DPNH- and the reduced form of triphosphopyridine nucleotide (TPNH)-cytochrome c reductases, transhydrogenase, and isocitric and lactic dehydrogenases were also examined. There was found a significantly higher myoglobin concentration in the muscle of the high-altitude native as compared with the sea-level resident. The enzyme systems DPNH-oxidase, TPNH-cytochrome c reductase, and transhydrogenase similarly showed a significantly higher activity in the altitude resident. It was concluded that the respiratory capacity of the muscle was apparently higher in the altitude native than in the sea-level one. The enhanced enzymatic activity was probably related to the higher pigment content of the skeletal muscle. Results on myoglobin determinations in several other muscles from certain sea-level patients are discussed. Submitted on July 24, 1961

scholarly journals Cohort profile: the MCC-Spain follow-up on colorectal, breast and prostate cancers: study design and initial results

BMJ Open ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. e031904 ◽  
Author(s):  
Jessica Alonso-Molero ◽  
Antonio J Molina ◽  
Jose Juan Jiménez-Moleón ◽  
Beatriz Pérez-Gómez ◽  
Vicente Martin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Clinical Stage ◽  
Sociodemographic Factors ◽  
Cancer Prognosis ◽  
Stage Ii ◽  
Breast Cancers ◽  
Prostate Cancers ◽  
Incident Cases

PurposeSince 2016, the multicase-control study in Spain (MCC-Spain) has focused towards the identification of factors associated with cancer prognosis. Inception cohorts of patients with colorectal, breast and prostate cancers were assembled using the incident cases originally recruited.Participants2140 new cases of colorectal cancer, 1732 of breast cancer and 1112 of prostate cancer were initially recruited in 12 Spanish provinces; all cancers were incident and pathologically confirmed. Follow-up was obtained for 2097 (98%), 1685 (97%) and 1055 (94.9%) patients, respectively.Findings to dateInformation gathered at recruitment included sociodemographic factors, medical history, lifestyle and environmental exposures. Biological samples were obtained, and 80% of patients were genotyped using a commercial exome array. The follow-up was performed by (1) reviewing medical records; (2) interviewing the patients by phone on quality of life; and (3) verifying vital status and cause of death in the Spanish National Death Index. Ninety-seven per cent of recruited patients were successfully followed up in 2017 or 2018; patient-years of follow-up were 30 914. Most colorectal cancers (52%) were at clinical stage II or lower at recruitment; 819 patients died in the follow-up and the 5-year survival was better for women (74.4%) than men (70.0%). 71% of breast cancers were diagnosed at stages I or II; 206 women with breast cancer died in the follow-up and the 5-year survival was 90.7%. 49% of prostate cancers were diagnosed at stage II and 32% at stage III; 119 patients with prostate cancer died in the follow-up and the 5-year survival was 93.7%.Future plansMCC-Spain has built three prospective cohorts on highly frequent cancers across Spain, allowing to investigate socioeconomic, clinical, lifestyle, environmental and genetic variables as putative prognosis factors determining survival of patients of the three cancers and the inter-relationship of these factors.

Endo-1, 4-β-glucanase and β-glucosidase of the ciliate Polyplastron multivesiculatum free of cellulolytic bacteria

1986 ◽  
Vol 32 (3) ◽  
pp. 219-225 ◽  
Author(s):  
A. Bonhomme ◽  
G. Fonty ◽  
M. J. Foglietti ◽  
D. Robic ◽  
M. Weber
Keyword(s):  
Enzymatic Activity ◽  
Isoelectric Focusing ◽  
Reducing Sugars ◽  
Proteolytic Enzymes ◽  
Cellulose Degradation ◽  
Protein Fractions ◽  
Intracellular Bacteria ◽  
Cellulolytic Bacteria ◽  
Derivatives Of ◽  
Bacterial Cellulase

To determine the contribution of protozoal activity to cellulose degradation, we maintained the ciliate Polyplastron multivesiculatum free of extracellular and intracellular cellulolytic bacteria. Control experiments to verify the absence of such bacteria were performed on cellular extracts, on filtrates, and on ciliates before lyophilization. The enzymatic activity was determined by viscometry and by determining the amount of reducing sugars produced. The enzyme was found to be an endo-1, 4- β-glucanase. Polyplastron multivesiculatum which was maintained free of extracellular and intracellular bacteria degraded soluble derivatives of cellulose and slightly degraded native cellulose. The activity was not due to intracellular bacterial cellulase, as ingested bacteria were lysed and digested by proteolytic enzymes of the protozoan. In addition, when preparing the filtrate solutions, P. multivesiculatum was maintained in culture for 5 days with Streptococcus faecalis (a facultatively anaerobic, noncellulolytic bacterium). Isoelectric focusing and chromatofocusing of lyophilized P. multivesiculatum that was free of cellulolytic bacteria yielded three protein fractions that degrade carboxymethylcellulose and hydroxyethylcellulose. Chromatofocusing also revealed the presence of two protein fractions with β-glucosidase activity.

Trial of the cysteine cathepsin inhibitor JPM-OEt on early and advanced mammary cancer stages in the MMTV-PyMT-transgenic mouse model

2008 ◽  
Vol 389 (8) ◽  
Author(s):  
Uta Schurigt ◽  
Lisa Sevenich ◽  
Corinne Vannier ◽  
Mieczyslaw Gajda ◽  
Anne Schwinde ◽  
...  
Keyword(s):  
Lung Metastases ◽  
Control Group ◽  
Breast Cancers ◽  
Cancer Trial ◽  
Tissue Extracts ◽  
Cysteine Cathepsins ◽  
Cysteine Cathepsin ◽  
Effective Inhibition ◽  
Pharmacokinetic Properties

Abstract Recent data suggest proteases of the papain-like cysteine cathepsin family as molecular targets for cancer therapy. Here, we report the treatment of polyoma middle T oncogene-induced breast cancers in mice with the cell-permeable broad-spectrum cysteine cathepsin inhibitor JPM-OEt. Up to 100 mg/kg inhibitor was intraperitoneally injected once per day in two trials on early and advanced cancers. In both trials, transient delays in tumour growth were observed. However, at the endpoint of both experiments no significant differences in tumour weights, histopathology and lung metastasis were found between the inhibitor and the control group. The invasive strand formation of collagen I-embedded tumour cell spheroids generated from primary tumours of inhibitor-treated mice in the early cancer trial could be inhibited in vitro by JPM-OEt; a result arguing against induction of resistance to the inhibitor. Measurement of cysteine cathepsin activities in tissue extracts after intraperitoneal injection of JPM-OEt revealed effective inhibition of cysteine cathepsins in pancreas, kidneys and liver, while activities in mammary cancers and in lungs were not significantly affected. We conclude that the pharmacokinetic properties of JPM-OEt, which result in poor bioavailability, may prohibit its use for stand-alone treatment of solid mammary cancers and their lung metastases.

scholarly journals The Epidemiology of Lung Metastases

2021 ◽  
Vol 8 ◽  
Author(s):  
Hanbo Chen ◽  
Kelsey C. Stoltzfus ◽  
Eric J. Lehrer ◽  
Samantha R. Horn ◽  
Shankar Siva ◽  
...  
Keyword(s):  
Lung Metastasis ◽  
De Novo ◽  
Lung Metastases ◽  
Statistical Significance ◽  
Incidence Rates ◽  
High Risk Population ◽  
Breast Cancers ◽  
Lung Cancers ◽  
Prostate Cancers ◽  
Poor Outcomes

Introduction: Lung metastasis is usually associated with poor outcomes in cancer patients. This study was performed to characterize and analyze the population of patients with de novo (synchronous) lung metastases using the Surveillance, Epidemiology and End Results (SEER) database.Materials and Methods: Baseline characteristics of lung metastasis patients were obtained from SEER case listings. Incidence rates and counts of synchronous lung metastasis were also obtained using the SEER*Stat software. Survival outcomes were analyzed using univariate and multivariable Cox regressions, controlling for confounders. An alpha threshold of 0.05 was used for statistical significance and p-values were subject to correction for multiple comparisons.Results: The age-adjusted incidence rate of synchronous lung metastasis was 17.92 per 100,000 between 2010 and 2015. Synchronous lung metastases most commonly arose from primary lung cancers, colorectal cancers, kidney cancers, pancreatic cancers and breast cancers. During this time period, 4% of all cancer cases presented with synchronous lung metastasis. The percentage of patients presenting with synchronous lung metastasis ranged from 0.5% of all prostate cancers to 13% of all primary lung cancers. The percentage of all cancer cases presenting with synchronous lung metastasis increased over time. De novo metastatic patients with lung metastases had worse overall survival [hazard ratio = 1.22 (1.21–1.23), p < 0.001] compared to those with only extrapulmonary metastases, controlling for potential confounders.Conclusions: Synchronous lung metastasis occurs frequently and is an independent predictors of poor patient outcomes. As treatment for lung metastases becomes more complicated, patients with synchronous lung metastasis represent a high-risk population.

Proteolytic activity of Oidiodendron kalrai

1975 ◽  
Vol 21 (9) ◽  
pp. 1362-1368 ◽  
Author(s):  
P. M. Cino ◽  
R. P. Tewari
Keyword(s):  
Basement Membrane ◽  
Enzymatic Activity ◽  
Human Serum ◽  
Proteolytic Activity ◽  
Crude Extract ◽  
Protease Activity ◽  
Proteolytic Enzymes ◽  
Cell Free Extract ◽  
Yeast Phase ◽  
Biological Substrates

The physiochemical characteristics of the intracellular proteolytic enzymes of Oidiodendron kalrai, a neuropathogenic fungus, were studied. The organism in the yeast phase was grown in a semisynthetic medium containing 1% tryptone, at 37 °C for 48 h, on a gyrotory shaker. The crude extract was prepared by breaking the cells in a French pressure cell and the proteolytic activity was tested against biological substrates. The cell-free extract hydrolyzed casein, hemoglobin, lactalbumin, gelatin, elastin, collagen, and purified rabbit renal basement membrane to various degrees. Optimal proteolytic activity was observed at pH 6 and at 32 °C. Calcium and EDTA did not affect the enzymatic activity; however, activity was partially inhibited by sulfhydryl-blocking agents and by heat-inactivated horse, calf, and human serum. The extract was totally inactivated by exposure to a temperature of 70 °C for 60 min. Storage at −76 °C or −15 °C for 6 months or at 4 °C for 4 weeks did not affect protease activity.

Cancer chemoprevention

2016 ◽  
pp. 262-266
Author(s):  
Hans-Joerg Senn ◽  
Nadir Arber ◽  
Dirk Schrijvers
Keyword(s):  
Cancer Risk ◽  
Cancer Chemoprevention ◽  
Malignant Neoplasms ◽  
Breast Cancers ◽  
Reductase Inhibitors ◽  
Cancer Occurrence ◽  
High Risk Populations ◽  
Cancer Types ◽  
Prostate Cancers

Cancer prevention certainly would be the best approach to cancer. Interventions should be effective, with minimal side effects, convenient, and inexpensive. Cancer chemoprevention is defined as the pharmacologic intervention with the process of carcinogenesis to prevent the development of overt malignant neoplasms in healthy individuals with elevated cancer risk. The present list of candidate cancer types for active chemoprevention is still short and includes SERMs (tamoxifen, raloxifene) and an aromatase-inhibitor (exemestane) for chemoprevention of breast cancers, showing significant reduction of cancer occurrence. The same holds true for reduction of the development of invasive cancers by aspirin, NSAIDs, and COX2-inhibitors in selected populations with increased colorectal cancer risk. There is also reduction of prostate cancers by long-term application of 5-alfa-reductase-inhibitors (finasteride, dutasteride) in selected high-risk populations. Many other potentially active anti-neoplastic compounds have been tested but do not meet all the criteria of efficiency, efficacy, and cost-effectiveness.

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