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 our study was to evaluate the association between the mammographic appearance and the biologic characteristics of high-grade breast carcinomas. Three hundred and twenty patients with breast carcinomas were studied. Histological examination showed 83 (26%) high-grade ductal carcinomas. Immunohistochemistry was carried out by using antibodies against estrogen receptor (ER), progesterone receptor (PR), HER-2/neu, p53 and cathepsin D. In 60/83 high-grade carcinomas we studied the mammographic appearance. Asymmetric density with poorly defined margins without microcalcifications was the major mammographic finding in 49/60 (approximately 82%) high-grade ductal carcinomas. HER-2/neu positivity (68.7%) and p53 positivity (48.2%) were statistically correlated with asymmetric density with poorly defined margins without microcalcifications in high-grade carcinomas. We observed loss of ER and PR receptors in 50%, whereas loss of PR receptors was observed in 65% of high-grade breast carcinomas. Cathepsin D (> 20%) was detected in 38.5% of high-grade carcinomas. Our findings suggest a significant relationship between mammographic appearance and biologic markers in high-grade breast carcinomas.
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PMID:Correlation of mammographic appearance and molecular prognostic factors in high-grade breast carcinomas. 1655 Sep 66

Erythropoietin (Epo) and the epo-receptor (EpoR) have been implicated in tumor growth, invasion and metastasis. We previously demonstrated Epo and EpoR expression in a small group of archived papillary thyroid cancers (PTC), but were unable to examine functional integrity using formalin-fixed tissues. In the present study, we examined the in vitro expression, induction and function of Epo and EpoR in papillary (NPA), follicular (WRO) and anaplastic (ARO-81) thyroid cancer cells. We found that all three cell lines expressed Epo and EpoR mRNA and that the hypoxia-mimetic cobalt induced Epo expression in all cell lines. None of the growth factors we examined (thyrotropin, vascular endothelial growth factor, IGF-I, or human Epo) altered Epo or EpoR gene expression. Importantly, however, administration of Epo to NPA but not WRO cells resulted in significant alterations in the expression of several mitogenic genes including cyclooxygenase-2 (COX-2), beta-casein (CSN2), wild type p53-induced gene-1 (WIG1) and cathepsin D (CTSD). Epo treated ARO-81 cells only had an increase in CSN2 expression. We conclude that Epo and EpoR are expressed by thyroid cancers and that stimulation of the Epo/EpoR signal pathway results in changes that could impact on the clinical behavior of thyroid cancers.
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PMID:Erythropoietin in thyroid cancer. 1669 98

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

The variant cell lines stably expressing aryl hydrocarbon receptor repressor (AhRR), MCFRR1 and MCFRR4, were established from human breast cancer MCF-7 cells by transfecting with AhRR-expression construct followed by selection, in order to analyze the effect of AhRR on the cell growth and expression of cell cycle-related genes. The variant cells showed higher levels of AhRR mRNA compared with the parental cells. MCFRR4 cells grew slowly compared with MCF-7 in both cell number and proliferation rate measured by the MTS method. Among cell cycle-related genes such as E2F, cyclin E1, cyclin D1, PCNA, p53, Rb, c-myc and p27Kip1, and estrogen responsive genes such as cathepsin D and hsp27, the expression levels of E2F, cyclin E1, PCNA and cathepsin D mRNA in MCFRR4 cells were lower than those in MCF-7 cells, while those of Rb, p27Kip1, c-myc and hsp27 mRNA were not significantly affected and that of cyclin D1 mRNA was enhanced in variant cells. Based on these results, AhRR might be suppressive on cell growth of MCF-7 by disturbing the transcriptional and/or posttranscriptional regulations of estrogen-responsive and cell cycle-related genes.
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PMID:The inhibitory effect of aryl hydrocarbon receptor repressor (AhRR) on the growth of human breast cancer MCF-7 cells. 1675 28

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

Novel therapeutic strategies are needed to address the emerging problem of imatinib resistance. The histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) is being evaluated for imatinib-resistant chronic myelogenous leukemia (CML) and has multiple cellular effects, including the induction of autophagy and apoptosis. Considering that autophagy may promote cancer cell survival, we hypothesized that disrupting autophagy would augment the anticancer activity of SAHA. Here we report that drugs that disrupt the autophagy pathway dramatically augment the antineoplastic effects of SAHA in CML cell lines and primary CML cells expressing wild-type and imatinib-resistant mutant forms of Bcr-Abl, including T315I. This regimen has selectivity for malignant cells and its efficacy was not diminished by impairing p53 function, another contributing factor in imatinib resistance. Disrupting autophagy by chloroquine treatment enhances SAHA-induced superoxide generation, triggers relocalization and marked increases in the lysosomal protease cathepsin D, and reduces the expression of the cathepsin-D substrate thioredoxin. Finally, knockdown of cathepsin D diminishes the potency of this combination, demonstrating its role as a mediator of this therapeutic response. Our data suggest that, when combined with HDAC inhibitors, agents that disrupt autophagy are a promising new strategy to treat imatinib-refractory patients who fail conventional therapy.
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PMID:Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance. 1736 33

The aim of this paper is to determine similarities and differences between tumor cell subclones in cases of ductal invasive breast carcinoma, and which occupy primary tumor and local axillary lymph metastases. The tumor growth fraction evaluated by Ki-67 was analyzed along with the expression level of estrogen and progesterone receptors, protein p53, proto-oncogene protein bcl-2 and cathepsin D in 60 patients. Metastatic lymph node in axilla has a higher growth fraction of the tumor cells than the primary tumor (p = 0.045), as well as the higher level of bcl-2 overexpression (p = 0.014). No statistically significant difference was found in the presence of immunohistochemically identified estrogen receptors (p = 0.161) and progesterone receptors (p = 0.081) between the primary tumor and the metastatic lymph node in axilla. Likewise, no difference was found between the immunohistochemical evaluation of p53 (p = 0.356) and cathepsin D activity (p = 0.928). A higher growth fraction of the tumor cells and the higher level of bcl-2 overexpression in metastatic tumor cells indicate the more aggressive cell subclones. This study does not support the routine testing of both primary tumor and locoregional metastasis to evaluate the breast cancer hormone receptor status.
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PMID:Tumor growth fraction, expression of estrogen and progesterone receptors, p53, bcl-2 and cathepsin D activity in primary ductal invasive breast carcinoma and their axillary lymph node metastases. 1821 56

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.
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PMID:Resveratrol: a multitargeted agent for age-associated chronic diseases. 1841 53

The Francisella tularensis strain LVS phagosome disintegrates during the first few hours after bacterial entry and microbes are released to the cytosol. Within 12 h both rapid multiplication of microbes and a steep increase of apoptosis of infected macrophages occur. We searched for signals involved in the death of macrophages and detected molecules associated with the autophagy machinery cathepsin D, PTEN, p53 and LC3, whose levels or modification were influenced by ongoing in vitro tularemic infection. The sequestration of cytoplasmic F. tularensis LVS into autophagosomes was confirmed by co-localization of the LVS strain containing vacuoles with LC3 (an autophagosomal marker). We also demonstrated the presence of MHC II antigens in these autophagosomes, indicating that they might act as a source of endogenous tularemic antigens for presentation to CD4+ T lymphocytes.
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PMID:Francisella tularensis strain LVS resides in MHC II-positive autophagic vacuoles in macrophages. 1845 Feb 26

We studied the effect of age and melatonin on cell death processes in brain aging. Senescence-accelerated prone mice 8 (SAMP8) and senescence-accelerated resistant mice (SAMR1) at 5 and 10 months of age were used as models of the study. Melatonin (10 mg/kg) or its vehicle (ethanol at 0.066%) was administered in the drinking water from 1 to 9 months of age. Neurodegeneration, previously shown in the aged brain of SAMP8 and SAMR1 at 10 months of age, may be due to a drop in age-related proteolytic activities (cathepsin D, calpains, and caspase-3). Likewise, lack of apoptotic and macroautophagic processes were found, without apparent modification by melatonin. However, the caspase-independent cell death, owing to high p53 and apoptosis-inducing factor (AIF) levels, might be an alternative pathway of cell death in the aged brain. The main effects of melatonin treatment were observed in the aged SAMR1 mice; in this strain we observed a marked increase in antioxidant activity (catalase and superoxide dismutase). Likewise, a key antioxidant role of apoptosis-related proteins, Bcl-2 and AIF, was suggested in the aged brain of SAM mice, which was clearly influenced by melatonin. Moreover, the age-related increase of lysosomal activity of cathepsin B and a lysosomal membrane-associated protein 2 supports the possibility of the maintenance of lysosomal viability in addition to age-related impairments of the proteolytic or macroautophagic activities. The effectiveness of melatonin against the oxidative stress-related impairments and apoptosis during the aging process is, once more, corroborated in this article.
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PMID:Melatonin alters cell death processes in response to age-related oxidative stress in the brain of senescence-accelerated mice. 1909 Sep 13


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