Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ki-67 immunoreactivity was studied in relation to immunohistochemically assessed expression of epidermal-growth-factor receptor (EGFR), estrogen receptor (ER) progesterone receptor (PgR) and cytosolic levels of cathepsin D in advanced human ovarian adenocarcinomas, borderline and benign cystadenomas and normal ovaries. A significantly higher number of Ki-67-positive cells were found in metastatic tumors vs. primary adenocarcinomas and in the total group of adenocarcinomas vs. benign/borderline cystadenomas. Cathepsin-D levels were also significantly higher in metastatic tumors than in primary adenocarcinomas, which in turn presented higher levels than were found in normal ovaries. However, no significant difference was observed between cathepsin-D levels in malignant adenocarcinomas and borderline/benign cystadenomas. Immunohistochemically assessed expression of ER and PgR was detected in variable percentages of epithelial tumor cells, and stromal cells were occasionally positive as well. In the group of primary adenocarcinomas, 46% were ER-positive and 34% were PgR-positive, although there was no significant difference between primary and metastatic lesions with respect to ER or PgR expression. Concordance between immunohistochemically assessed ER or PgR data and cytosolic ER and PgR levels measured with enzyme immunoassay was relatively low. EGFR, immunohistochemically assessed with MAb-EGFRI, was positive in 76% of the primary and in 78% of the metastatic adenocarcinomas. A strong positive association was detected between ER and PgR, and EGFR was observed to present a weak positive correlation with Ki-67 and ER. Cathepsin-D levels were not found to be significantly correlated with the expression of ER, PgR, EGFR or Ki-67.
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PMID:Ki-67 staining in benign, borderline, malignant primary and metastatic ovarian tumors: correlation with steroid receptors, epidermal-growth-factor receptor and cathepsin D. 818 51

Cathepsin D is an acidic lysosomal protease expressed in all cells. Some studies have shown correlations between high levels of tissue cathepsin D and poor prognosis. This paper deals with 158 cases of breast cancer in which tissue concentrations in cathepsin D, age, estrogen and progesterone receptor content, and pathological characteristics of the tumor were investigated. Tumors were considered to be cathepsin D+ when a concentration > 40 pmol/mg protein (median value in our samples) was determined. The expression of cathepsin D appears to be related to grading (p = 0.04) and lymph node status (p = 0.05). We found no significant associations among cathepsin D levels, patient age, steroid receptors and histological type. Moreover, the levels of cathepsin D have been evaluated in 9 samples of recurring or metastatic neoplasia and 11 cases of benign breast lesions. We conclude that cathepsin D may be a useful prognostic predictor in breast cancer. Further investigations are required to improve and extend the applications of this assay.
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PMID:Evaluation of cathepsin D as prognostic predictor in breast cancer. 820 15

Immunocytochemical assays of cathepsin D were assessed in a series of breast carcinomas (n = 257) using monoclonal M1G8 anti-total cathepsin D and the avidin-biotin-peroxidase complex. Cathepsin immunoreactivity was compared in frozen and paraffin sections. All tumours were anti-cathepsin-positive. Positive staining was observed in carcinoma and stromal cells and in the extracellular matrix. The amount of immunodetectable cathepsin in tissue was measured by computer-assisted image analysis (SAMBA 2005). Both the percentage of immunostained tumour surface and the mean optical densities were processed as continuous variables for statistical analysis and correlated with prognostic factors. It was shown that cathepsin D was independent of the tumour size, the lymph node status, hormone receptors, and pHER-2/neu overexpression. Cathepsin was significantly correlated with anti-EGFR (P = 0.012) and Ki67 (P = 0.002) immunoreactivity, tumour grade (P = 0.032), vascular invasion (P = 0.0081), proliferation index (P = 0.0045), and, to a lesser extent with AgNORs (P = 0.0504) and the degree of hyperploidy (P = 0.057). Tissue fixation and paraffin embedding significantly decreased cathepsin immunoreactivity. These results show that cathepsin D is not a totally independent prognostic factor in breast carcinomas.
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PMID:Cathepsin D immunocytochemical assays in breast carcinomas: image analysis and correlation to prognostic factors. 841 Apr 96

The aspartyl protease cathepsin D has been shown to be a marker of poor prognosis when found at high levels in primary breast tumors. It has been suggested that this is because the production of cathepsin D increases the invasive potential of the tumor cells, thus increasing the probability of metastasis. We have therefore conducted experiments to determine if secreted cathepsin D makes a significant contribution to the invasive phenotype of breast cancer cells in the Boyden chamber assay of invasion, which measures the ability of a cell to invade through an artificial basement membrane. Cathepsin D secretion and Boyden chamber invasiveness were measured in nine clones of the breast cancer cell line MCF-7, and no correlation was found between cathepsin secretion and invasive behavior. Invasion assays were also conducted in the presence of the aspartyl protease inhibitor pepstatin A, and no inhibition of the invasive behavior of cells was seen. Since low-pH environments are required for both the activation of pro-cathepsin D and the activity of the mature enzyme, assays were also conducted in the presence of chloroquine to neutralize the pH in the acidic compartments of the cells. This treatment did not inhibit invasiveness. Cathepsin D secretion by the breast cancer cell lines MDA-MB-231, MDA-MB-435, MDA-MB-435s, MDA-MB-468, SK-Br-3, and MCF-7-ADRr was also measured. Again, there was no correlation with invasion. In fact, cathepsin D levels were inversely correlated with aggressive behavior in vivo and in vitro in previously reported studies. These data suggest that cathepsin D secretion by tumor cells is not an important determinant of the invasiveness of the tumor cells per se. These data also reinforce the view that the poor prognosis in clinical breast cancer linked to high tumor levels of cathepsin D is probably due to high levels of cathepsin D in the stromal components of the tumor such as infiltrating inflammatory cells.
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PMID:The role of cathepsin D in the invasiveness of human breast cancer cells. 842 68

It has been suggested that cathepsin D expression in stromal cells affects the prognosis of breast cancer. With reference to colon and breast cancer, this study verified cathepsin D immunostaining in epithelial and stromal cells of primary tumours and lymph-node metastases from 46 colorectal carcinomas. Eight of 46 cases (17%) were cathepsin D+ both in cancer and stromal cells. No staining was found either in cancer or stromal cells of the remaining cases. The results presented here suggest the possible paracrine influence of another diffusible factor produced by cancer cells which stimulates cathepsin D production in stromal and cancer cells.
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PMID:The immunohistochemical expression of cathepsin D in colorectal cancer. 861 73

MHC class II molecules associate with peptides in the endocytic pathway. Different endosomal locations for peptide loading of class II molecules, varying from early endosomes (EE) to lysosomes, have been assigned on the basis of subcellular fractionation experiments. We have determined the intracellular location of HLA-DM, a molecule that supports peptide loading of class II molecules, by separating vesicles from the melanoma cell line Mel JuSo on the basis of buoying density and surface charge. In both fractionations, HLA-DM co-fractionated with a lysosomal compartment containing beta-hexosaminidase (beta-hex) activity and not with endosomes. Further analysis showed that HLA-DM mainly co-fractionated with a sub-lysosomal structure characterized by a relative low density and containing both pro- and mature cathepsin D and MHC class II molecules. Fluid phase markers first enter this compartment before entering high-density lysosomes that contain exclusively mature cathepsin D, some HLA-DM and no detectable MC class II molecules. Finally we determined the intracellular location of neutral and acidic peptidases. Whereas neutral peptidase activity was detected in the endoplasmic reticulum and/or plasma membrane fractions, acidic peptidase activity exclusively migrated at the position of HLA-DM containing lysosomal vesicles. Our results show that class II molecules co-migrate with HLA-DM, pro- and mature cathepsin D, beta-hex and acidic peptidase activity. HLA-DM, cathepsin d and class II molecules were not observed at the position of EE. Our data suggest that HLA-DM-mediated peptide loading of class II molecules occurs in a lysosomal subcompartment.
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PMID:HLA-DM and MHC class II molecules co-distribute with peptidase-containing lysosomal subcompartments. 867 50

It was found that subretinal fluid contains at least two different proteolytic enzymes which digest various protein substrates. The main of them was identified as cathepsin D. This protease is very active towards the denatured haemoglobin. The highest activity is apparent at pH 3-4 and it is completely inhibited by the action of pepstatin. The cathepsin activity increases with the duration of retinal detachment. The other proteolytic enzyme acts at slightly alkaline pH. Its activity is lower and does not change with the duration of the disease.
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PMID:Cathepsin D and an alkaline protease activities in subretinal fluid. 883 22

We have determined the primary cleavage sites in the bone Gla protein (BGP; osteocalcin) for several of the proteases that could act on the protein during bone resorption and turnover, cathepsins B, D, L, H, and S. The time course of BGP digestion by each cathepsin was first determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. We then incubated human and bovine BGP with each cathepsin for a sufficient time to reduce the level of intact protein by at least 20-fold, isolated the major cleavage peptides, and identified each by N-terminal sequence analysis and by amino acid analysis. Our results show that BGP has relatively few cathepsin-sensitive sites and that these sites are located at the N and C terminus of the 49-residue protein. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42. The immunoreactivity of the major peptides generated by cathepsin cleavage was evaluated using the original radioimmunoassay developed for the detection of BGP in human serum. The BGP 8-49 fragment cross-reacts identically with native BGP, while the 8-43 and the 1-44 fragments require 20- to 40-fold higher concentrations to achieve the same level of displacement as the native protein. The 1-41 and 8-41 fragments are unable to significantly displace the labeled native BGP tracer at any concentration tested. These results demonstrate the utility of peptides generated by cathepsin digestion in the mapping of the antigenic epitopes recognized by a given BGP immunoassay.
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PMID:Identification of peptide fragments generated by digestion of bovine and human osteocalcin with the lysosomal proteinases cathepsin B, D, L, H, and S. 907 88

In this study, we demonstrate insulin-like growth factor binding protein (IGFBP) acid proteolysis in conditioned media (CM) from normal and malignant primary cultures of prostatic epithelial cells, prostatic cell lines, and in seminal plasma. We further demonstrate the absence of such activity in CM from prostatic stromal cells. Radio-labeled IGFBPs (1-6) were incubated with various acidified CM and seminal plasma. None of these media showed IGFBP proteolytic activity at neutral pH, but all CM from prostatic epithelial cells (PC-E) demonstrated strong IGFBP proteolysis at acidic pH. No acid-activated proteolysis was observed in the CM from stromal cell cultures. In order to ascertain the role of cathepsin D, anti-cathepsin antibodies were used to immunodeplete the media of the selected enzymes prior to incubation with IGFBPs. Depletion of cathepsin D greatly reduced the proteolytic activity of the PC-E CM. Additionally, purified cathepsin D yielded a digestion pattern identical to that produced by prostatic cell CM and seminal plasma, following acidic incubation with IGFBP-3. Remarkably, the proteolytic pattern generated by seminal plasma, when incubated with IGFBP-3 at neutral pH, corresponded to that produced by prostate-specific antigen (PSA), demonstrating the interpolation of both neutral and acid proteases from prostate cells into seminal plasma. In conclusion, prostatic epithelial cells secrete acid-specific IGFBP protease(s) related to cathepsin D. Although no significant statistical difference was observed in the degree of acid-specific proteolysis in the media from normal versus malignant primary epithelial cell cultures, physiological characteristics of the malignant state might facilitate increased cathepsin D activity. We suspect this proteolysis may play a role in prostatic cell proliferation and invasive tumor growth.
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PMID:Acid-activated insulin-like growth factor binding protein protease activity of cathepsin D in normal and malignant prostatic epithelial cells and seminal plasma. 913 Apr 67

The value of cathepsin D determinations done on tumor cytosols in evaluating the prognosis of breast cancer patients has been debated in the literature. Our previous work suggested that cathepsin D determinations were not of prognostic value, but in that study we used immunoblotting and immunohistochemical methods rather than the more widely used double antibody immunoradiometric (IRMA) assay for measuring cathepsin levels. Here we report our results determining cathepsin D using components of a commercially available IRMA system on a large patient sample (n = 1984). Reagents from a commercially available IRMA kit were used to analyze cathepsin D levels in the cytosols of 1984 patients with breast cancer. All patients had invasive breast cancer with known tumor size and with some axillary nodes pathologically examined. Only patients with T1 and T2 tumor sizes were included. Median follow-up was 37 months. The hypothesis that high cathepsin D levels correlated with poorer outcome (poorer DFS or OS) was not confirmed, either in all patients, or in node-positive or node-negative subsets. Only in patients treated with adjuvant therapy were higher cathepsin D levels correlated with negative outcome (worsened OS, but not DFS), although given the large number of subsets analyzed this correlation may be spurious. Multivariate analyses using interaction terms did not support the concept that high cathepsin D levels correlate with resistance to adjuvant therapy. In this study evaluating the value of cathepsin D using components from a kit widely used for measuring cathepsin D levels, we conclude that cathepsin D is of doubtful value in predicting risk of early relapse or death for patients with newly diagnosed invasive breast cancer.
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PMID:Lack of prognostic value of cathepsin D levels for predicting short term outcomes of breast cancer patients. 921 61


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