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)

The aim of this study was to investigate the role of cathepsin D in colorectal cancer. For this purpose cathepsin D expression was evaluated by means of immunohistochemistry in stromal and tumor cells of 31 colorectal carcinomas and 29 adenomas. Cytoplasmic cathepsin D expression of tumor cells was present in 90.3% of the carcinoma cases and various degrees of stromal cell cathepsin D expression were present in all cases. In the adenomas, the epithelial cells and stromal cells expressed cathepsin D in 68.96% and 96.55% of cases, respectively. The staining intensity was always weaker in the adenomas. When the stromal and tumor cell cathepsin D expression in the adenocarcinoma and adenoma cases were compared, a statistically significant difference was observed in the staining of stromal cells. Furthermore, stromal cathepsin D expression in the adenocarcinomas was related to tumor stage when the carcinomas were divided into low and high stage. Cathepsin D expression in stromal cells may be an important indicator of poor prognosis in colorectal adenocarcinomas.
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PMID:Cathepsin D expression in colorectal adenocarcinomas and adenomas. 1240 66

Lysosomal proteinases, cathepsin B (CB) and cathepsin D (CD) have been implicated in the progression of several human tumors. In the present study, the antigen levels of CB and CD, and their immunohistochemical staining were compared in paired colorectal tumors (n =64) and background colon tissue of the same patients with clinicopathological staging. The antigen levels, were found to be significantly higher in cancer tissue (mean 35.79 ng/mg protein for CB and 3.97 ng/mg protein for CD) than in corresponding normal mucosa (24.62 ng/mg protein for CB and 2.69 ng/mg protein for CD). CB antigen levels were positively correlated with differentiation grade and Duke's stage (P < 0.001 and P = 0.041, respectively), but not correlated with nodal status. CD antigen levels were not correlated with the previous parameters. Staining intensity for both antigens increased from adenoma to adenocarcinoma. The degree of staining for CB and CD was associated with differentiation grade (P = 0.004 and 0.001, respectively), Dukes' stage (P = 0.002 and 0.001, respectively) and lymph node involvement (P = 0.002 and P < 0.001, respectively).
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PMID:Cathepsin B and cathepsin D expression in the progression of colorectal adenoma to carcinoma. 1503 66

Pancreatic cancer is a rapidly fatal disease, and there is an urgent need for early detection markers and novel therapeutic targets. The current study has used a proteomic approach of two-dimensional (2D) gel electrophoresis and mass spectrometry (MS) to identify differentially expressed proteins in six cases of pancreatic adenocarcinoma, two normal adjacent tissues, seven cases of pancreatitis, and six normal pancreatic tissues. Protein extracts of individual sample and pooled samples of each type of tissues were separated on 2D gels using two different pH ranges. Differentially expressed protein spots were in-gel digested and identified by MS. Forty proteins were identified, of which five [i.e., alpha-amylase; copper zinc superoxide dismutase; protein disulfide isomerase, pancreatic; tropomyosin 2 (TM2); and galectin-1] had been associated previously with pancreatic disease in gene expression studies. The identified proteins include antioxidant enzymes, chaperones and/or chaperone-like proteins, calcium-binding proteins, proteases, signal transduction proteins, and extracellular matrix proteins. Among these proteins, annexin A4, cyclophilin A, cathepsin D, galectin-1, 14-3-3zeta, alpha-enolase, peroxiredoxin I, TM2, and S100A8 were specifically overexpressed in tumors compared with normal and pancreatitis tissues. Differential expression of some of the identified proteins was further confirmed by Western blot analyses and/or immunohistochemical analysis. These results show the value of a proteomic approach in identifying potential markers for early diagnosis and therapeutic manipulation. The newly identified proteins in pancreatic tumors may eventually serve as diagnostic markers or therapeutic targets.
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PMID:Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry. 1560 67

Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) and poly(ethylene glycol) (PEG)-grafted PHEG conjugates of N,N-di(2-chloroethyl)-4-phenylenediamine mustard (PDM) were synthetised. A collagenase-sensitive oligopeptide spacer was selected to link the cytotoxic agent PDM onto the polymeric carrier. First, the oligopeptide-drug conjugate, L-pro-L-leu-gly-L-pro-gly-PDM, was prepared. In a second step, the low molecular weight PDM derivative and PEG-NH(2) were coupled to a N,N-disuccinimidylcarbonate activated PHEG. Dynamic laser light scattering measurements indicated the formation of aggregates. The presence of human serum albumin had no significant effect on the diameter of the conjugates. The hydrolytic stability of the conjugates was investigated in buffer solutions. The conjugates showed an improved stability compared to the parent nitrogen mustard. The enzymatic degradation studies of the polymeric conjugates were performed in the presence of collagenase type IV (Clostridiopeptidase A; EC 3.4.24.3), cathepsin B (EC 3.4.22.1), cathepsin D (EC 3.4.23.5) and tritosomes. Only the bacterial collagenase type IV was able to cleave the spacer releasing free PDM and its peptidyl derivative, gly-L-pro-gly-PDM. The in vitro cytotoxicity of the conjugates was evaluated against HT1080 fibrosarcoma cells and MDA adenocarcinoma cells. All conjugates showed low toxicity towards these cell lines.
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PMID:Synthesis and in vitro evaluation of macromolecular antitumour derivatives based on phenylenediamine mustard. 1566 87

The aim of our study was to evaluate the association between the expression of cathepsin D and clinical prognostic data in endometrioid adenocarcinoma of different histological grade. We studied 104 postmenopausal women with diagnosis of endometrioid adenocarcinoma. We evaluated the presence of obesity and vaginal bleeding. Surgical specimens were fixed in 10% neutral buffered formalin solution and embedded in paraffin. 4 mm sections were stained by hematoxylin and eosin, von Gieson, and histological type of cancer, metastatic lesion of lymph nodes and depth of myometrial invasion were evaluated. Histological grade of cancer was assessed by FIGO grading system. All samples were analysed by immunohistochemistry for cathepsin D (Dakocytomation). We assessed the number of cathepsin D-positive stromal and tumor cells and degree of positivity (low, moderate, high). Histological study by hematoxylin and eosin showed grade 1 endometrioid carcinoma in 35 cases (33,7%, group 1), grade 2 in 44 cases (42,3%, group 2), grade 3 in 25 cases (24%, grade 3). Our results suggest that the expression of cathepsin D is associated with the higher histological grade of endometrioid adenocarcinoma, depth of myometrial invasion, lymph node positivity, coexistence of obesity and vaginal bleeding. It seems that local invasion and metastatic spread of tumor should be preceeded by the expression of cathepsin D in stromal cells which can be assessed in grade 1 and 2 endometrioid adenocarcinomas. The expression of cathepsin D can be used as a prognostic factor and more aggressive chemothepery regimen should be used.
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PMID:Clinical prognostic factors and expression of cathepsin D in endometrioid adenocarcinoma. 1623 88

WEB-2086 -- an antagonist of platelet-activating factor receptor (PAFR) with known anti-inflammatory, antiangiogenic and antileukaemic properties -- also proved to inhibit the proliferation in human solid tumour cell lines of different histology, and with much higher efficacy than in normal fibroblasts. A detailed analysis of WEB-2086 anticancer activity was then performed focusing on breast adenocarcinoma MCF-7 and MDA-MB-231 cells. WEB-2086-treated cells, either expressing (MCF-7) or unexpressing (MDA-MB-231) the oestrogen receptor (ER)alpha, underwent a dose-dependent growth arrest (IC(50)=0.65+/-0.09 and 0.41+/-0.07 mM, respectively) and accumulation in G(0)-G(1) phase. WEB-2086 also induced morphological and functional changes typical of mature mammary phenotype including (i) cell enlargement and massive neutral lipid deposition (best accomplished in MCF-7 cells); (ii) decrease in motility and active cathepsin D levels (mainly observed in highly invasive MDA-MB-231 cells). The expression of ERalpha was neither increased nor reactivated in treated MCF-7 or MDA-MB-231 cells, respectively. WEB-2086-induced differentiation in breast cancer cells involved the upregulation of PTEN, a key tumour suppressor protein opposing tumorigenesis, and was apparently independent of p53, PAFR, peripheral benzodiazepine receptor and ERalpha status. Overall, WEB-2086 can be proposed as an effective antiproliferative and differentiative agent with interesting translational opportunities to treat breast cancers in support to conventional chemotherapy.
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PMID:Growth inhibition and differentiation of human breast cancer cells by the PAFR antagonist WEB-2086. 1672 73

Lipofuscin, known as the "wear and tear" pigment, is seen in cells undergoing regressive changes, the seminal vesicles and the ejaculatory ducts. It is also present in prostatic adenocarcinoma. The purpose of this study is to evaluate the prognostic significance of lipofuscin in prostatic adenocarcinoma. Lipofuscin was evaluated in 736 hematoxylin-eosin-stained slides from 60 conventional and whole-mounted consecutive radical prostatectomies from December 1996 to February 2002. The adenocarcinoma cases were divided into lipofuscin-positive group and lipofuscin-negative group. The Gleason score and pathologic stage were compared between the 2 groups. Percentage of cells positive for p53 and MIB-1 was also compared. Lipofuscin pigment was found in 17 (31%) of 60 prostatic adenocarcinomas as random, sparse, fine, yellow-brown intracytoplasmic granules staining positive for cathepsin D and negative for S-100 protein. Using logistic regression to exclude age as a confounding factor, lower Gleason scores and pathologic stages were demonstrated in the lipofuscin-positive group. There was also a significant difference between the 2 groups in tumor volume, degree of capsular invasion, and positive margins. The difference in seminal vesicle invasion and vascular invasion between the 2 groups was not statistically significant. Lipofuscin in prostatic adenocarcinoma correlates with both lower Gleason score and pathologic stage. Lipofuscin probably indicates slow cellular turnover as suggested by the low proliferation rate and p53 expression. The value of lipofuscin in biopsy as a predictor separating aggressive from indolent disease needs further investigation.
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PMID:Lipofuscin pigment can be used as a prognostic marker in prostatic adenocarcinoma. 1697 16

Helicobacter pylori colonizes the gastric epithelium of at least 50% of the world's human population, playing a causative role in the development of chronic gastritis, peptic ulcers, and gastric adenocarcinoma. Current evidence indicates that H. pylori can invade epithelial cells in the gastric mucosa. However, relatively little is known about the biology of H. pylori invasion and survival in host cells. Here, we analyze both the nature of and the mechanisms responsible for the formation of H. pylori's intracellular niche. We show that in AGS cells infected with H. pylori, bacterium-containing vacuoles originate through the fusion of late endocytic organelles. This process is mediated by the VacA-dependent retention of the small GTPase Rab7. In addition, functional interactions between Rab7 and its downstream effector, Rab-interacting lysosomal protein (RILP), are necessary for the formation of the bacterial compartment since expression of mutant forms of RILP or Rab7 that fail to bind each other impaired the formation of this unique bacterial niche. Moreover, the VacA-mediated sequestration of active Rab7 disrupts the full maturation of vacuoles as assessed by the lack of both colocalization with cathepsin D and degradation of internalized cargo in the H. pylori-containing vacuole. Based on these findings, we propose that the VacA-dependent isolation of the H. pylori-containing vacuole from bactericidal components of the lysosomal pathway promotes bacterial survival and contributes to the persistence of infection.
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PMID:Helicobacter pylori VacA toxin promotes bacterial intracellular survival in gastric epithelial cells. 1700 Jul 20

We previously reported that N-(4-hydroxyphenyl)retinamide (4HPR) inhibits retinoblastoma tumor growth in a murine model in vivo and kills Y79 retinoblastoma cells in vitro. In this work, we assayed different cell death-related parameters, including mitochondrial damage and caspase activation, in Y79 cells exposed to 4HPR. 4HPR induced cytochrome c release from mitochondria, caspase-3 activation, and oligonucleosomal DNA fragmentation. However, pharmacologic inactivation of caspases by the pan-caspase inhibitor BOC-D-fmk, or specific caspase-3 inhibition by Z-DEVD-fmk, was not sufficient to prevent cell death, as assessed by loss of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction, lactate dehydrogenase release, disruption of mitochondrial transmembrane potential (Deltapsi(m)), and ATP depletion. We found that 4HPR causes lysosomal membrane permeabilization and cytosolic relocation of cathepsin D. Pepstatin A partially rescued cell viability and reduced DNA fragmentation and cytosolic cytochrome c. The antioxidant N-acetylcysteine attenuated cathepsin D relocation into the cytosol, suggesting that lysosomal destabilization is dependent on elevation of reactive oxygen species and precedes mitochondrial dysfunction. Activation of AKT, which regulates energy level in the cell, by the retinal survival facto]r insulin-like growth factor I was impaired and insulin-like growth factor I was ineffective against ATP and Deltapsi(m) loss in the presence of 4HPR. Lysosomal destabilization, associated with mitochondrial dysfunction, was induced by 4HPR also in other cancer cell lines, including PC3 prostate adenocarcinoma and the vascular tumor Kaposi sarcoma KS-Imm cells. The novel finding of a lysosome-mediated cell death pathway activated by 4HPR could have implications at clinical level for the development of combination chemoprevention and therapy of cancer.
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PMID:Novel cell death pathways induced by N-(4-hydroxyphenyl)retinamide: therapeutic implications. 1723 88

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers largely due to disseminated disease at the time of presentation. Here, we investigated the role and mechanism of action of the metastasis-associated protein anterior gradient 2 (AGR2) in the pathogenesis of pancreatic cancer. AGR2 was induced in all sporadic and familial pancreatic intraepithelial precursor lesions (PanIN), PDACs, circulating tumor cells, and metastases studied. Confocal microscopy and flow cytometric analyses indicated that AGR2 localized to the endoplasmic reticulum (ER) and the external surface of tumor cells. Furthermore, induction of AGR2 in tumor cells regulated the expression of several ER chaperones (PDI, CALU, RCN1), proteins of the ubiquitin-proteasome degradation pathway (HIP2, PSMB2, PSMA3, PSMC3, and PSMB4), and lysosomal proteases [cathepsin B (CTSB) and cathepsin D (CTSD)], in addition to promoting the secretion of the precursor form pro-CTSD. Importantly, the invasiveness of pancreatic cancer cells was proportional to the level of AGR2 expression. Functional downstream targets of the proinvasive activity of AGR2 included CTSB and CTSD in vitro, and AGR2, CTSB, and CTSD were essential for the dissemination of pancreatic cancer cells in vivo. Taken together, the results suggest that AGR2 promotes dissemination of pancreatic cancer and that its cell surface targeting may permit new strategies for early detection as well as therapeutic management.
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PMID:AGR2 is a novel surface antigen that promotes the dissemination of pancreatic cancer cells through regulation of cathepsins B and D. 2194 70


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