Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between skeletal muscle aspartyl protease activity (APA) and wasting was investigated in male DBA/2 mice inoculated with L1210 tumor cells. Using the peptidic substrate H-Pro-Thr-Glu-Phe-Phe(NO2)-Arg-Leu-OH, which is specific for aspartyl proteases, proteases, proteolytic activity was detected in a number of tissues including muscle by using a crude extraction procedure for isolation of lysosomal enzymes. Biochemical characterization and increased muscle levels following either fasting or injection of endotoxin (ETX) suggest that the enzyme is likely cathepsin D. The wasting syndrome accompanying the tumor was measured by comparing the weight of the skinned hind limb in treated and control animals. DBA/2 mice inoculated intraperitoneally with L1210 cells developed multiple solid tumors in the peritoneum and ascites; maximal tumor burden was reached by 16 days. There was a significant reduction in hind limb weight (16 +/- 2%; mean +/- SE) and significant increase (31 +/- 8%) in muscle APA associated with the development of ascites and solid tumors. Plasma APA activity was substantially increased (240 +/- 33%), while liver and spleen APA were increased (10-20%) but not significantly. Chronic pepstatin administration, 30 mg.kg-1.day-1, for 7 days concurrent with the initiation of observable ascites and solid tumor formation (7 days post-inoculation), completely inhibited hind limb weight loss and alleviated the tumor-dependent increase of APA in both plasma and muscle without altering tumor development. Delaying the administration of pepstatin by 3 days resulted in less of an inhibition (33 +/- 13%) of hind limb weight loss. Thus, cathepsin D or a similar aspartyl protease appears to be of key importance in the wasting syndrome associated with cachexia.
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PMID:Muscle aspartyl protease (cathepsin D) activity: detection using a chromophoric substrate and relation to wasting in DBA/2 mice implanted with leukemic L1210 tumor cells. 902 34

In tumor tissue specimens of 27 primary and 17 secondary glioblastomas and the precursor lesions, the immunohistochemical expression patterns of the membrane protein CD44s, the basal lamina proteins laminin, collagen IV, and fibronectin, the lectin galectin-3 recognizing tenascin and N-CAM as well as of the matrix-degrading enzymes matrix metalloproteinase MMP-2 and MMP-9, and cathepsin D were studied. Besides expression of basal lamina proteins in vessels, all glioblastomas and the precursor lesions showed strong immunoreactivity of CD44s, tenascin, galectin-3, and N-CAM which were restricted to solid tumor masses. Present in solid tumor areas, MMP-2, MMP-9 and cathepsin D were also strongly expressed by single tumors cells invading adjacent brain tissue at the infiltrative margin. Neither the expression pattern in primary and secondary glioblastomas nor in the precursor tumors revealed significant differences. There was also no intraindividual constant expression pattern during glioma progression or correlation with malignancy. Restricted expression of CD44s, galectin-3, tenascin and N-CAM in solid tumor masses seems to contribute to homotypic tumor cell adhesion while single tumor cells abolish this expression profile and acquire invasive activities by expression of cathepsin D, MMP-2 and MMP-9.
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PMID:Expression of adhesion factors and degrading proteins in primary and secondary glioblastomas and their precursor tumors. 1072 72

This study aims at the in situ identification of factors mediating glioma cell invasion requiring adhesion, extracellular matrix degradation, and migration. Forty-five gliomas (astrocytomas, glioblastomas, oligodendrogliomas, and mixed gliomas) were investigated for the immunohistochemical expression of the membrane protein CD44s, the basal lamina proteins laminin, collagen IV, and fibronectin, the lectin galectin-3 recognizing tenascin and N-CAM, as well as for the matrix-degrading enzymes metalloproteinases MMP-2, MMP-9, and cathepsin D. Besides vessels expressing basal lamina proteins, tenascin, MMP-2, MMP-9, and galectin-3, tumor cells revealed strong immunoreactivity for CD44s, tenascin, galectin-3, and N-CAM, which was restricted to solid tumor masses. Single invading cells displayed distinct expression of MMP-2 and MMP-9, also found in solid tumor areas, as well as of cathepsin D. Restricted expression of CD44s, galectin-3, tenascin, and N-CAM in solid tumor masses seems to contribute to homotypical tumor cell adhesion. However, switching to an invasive phenotype, single tumor cells lack this expression pattern and acquire degrading and phagocytic activities by expressing cathepsin D, MMP-2, and MMP-9, which are also expressed by solid tumor masses facilitating the loosening and invasion of single neoplastic cells. The blocking of these factors may be of potential benefit in anti-invasive therapy.
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PMID:Adhesive and invasive features in gliomas. 1108 57

The B16-F10 mouse model of melanoma is a widely used model to study many aspects of cancer biology and therapeutics in a solid tumor. Melanomas aggressively progress within a dynamic microenvironment containing in addition to tumor cells, stroma cells and components such as fibroblasts, immune cells, vascular cells, extracellular matrix (ECM) and extracellular molecules. The goal of this study was to elucidate the processes of tumor progression by identifying differentially expressed proteins in the tumor mass during specific stages of tumor growth. A comparative proteome analysis was performed on B16-F10 derived tumors in C57BL/6 mice at days 3, 5, 7, and 10. Statistical approaches were used to determine quantitative differential protein expression at each tumor time stage. Hierarchical clustering of 44 protein spots (p < 0.01) revealed a progressive change in the tumor mass when all 4 time stages were classified together, but there was a clear switch in expression of these proteins between the day 5 and the day 7 tumors. A trend analysis showed 53 protein spots (p < 0.001) following 6 predominant kinetic paths of expression as the tumor progressed. The protein spots were then identified using MALDI-TOF mass spectrometry. Proteins involved in glycolysis, inflammation, wounding, superoxide metabolism, and chemotaxis increased during tumorigenesis. From day 3 to day 7 VEGF and active cathepsin D were induced 7-fold and 4-fold, respectively. Proteins involved in electron transport, protein folding, blood coagulation, and transport decreased during tumorigenesis. This work illustrates changes in the biology of the B16-F10 tumor mass during tumor progression.
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PMID:Proteomic analysis of tumor establishment and growth in the B16-F10 mouse melanoma model. 1679 90

The small molecule b-AP15 is a novel inhibitor of proteasome deubiquitination. Recent studies have shown that b-AP15 displays antitumor activity in several preclinical, solid tumor models. In this study, we show that b-AP15 triggers time- and dose-dependent apoptosis of the human multiple myeloma (MM) cell lines RPMI8226 and U266, as determined by phosphatidylserine exposure. Apoptosis was dependent on caspase activation and was partially dependent on cathepsin D. Furthermore, b-AP15 triggered processing of pro-caspase-3 and cleavage of poly (ADP-ribose) polymerase in MM cells. b-AP15 also induced caspase-independent apoptosis in primary human natural killer cells. We also demonstrate that b-AP15 induces activation of the mitochondrial apoptosis pathway in MM cells, with activation of the proapoptotic protein Bax and a pronounced loss of the mitochondrial transmembrane potential. The latter events, however, appeared largely independent of caspase activation. Our data suggest that proteasome deubiquitinase inhibitors may have potential for treatment of multiple myeloma patients.
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PMID:Proapoptotic effects of the novel proteasome inhibitor b-AP15 on multiple myeloma cells and natural killer cells. 2429 87