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)

Human MDA-MB-231 derived breast cancer cell lines 1833 and 4175 have different metastatic potentials in terms of their tissue tropisms and aggressiveness. Cell line 1833 is specifically metastatic to the bone. The highly aggressive cell line 4175 is specific to the lung. We performed 2-DE analysis of the cell lines. We found 16 significantly changed protein spots, 14 protein spots were identified. Expression of cathepsin D, triosephosphate isomerase, phosphoglycerate kinase 1, heme binding protein 1 and annexin 2 could be correlated with the in vitro aggressiveness of the respective cell lines. Interstitial collagenase and dimethylargininase 2 were exclusive to the cell line 1833 and might contribute to its bone specificity. Serpin B9, cathepsin B chain b, galectin 3 and HSP 27 were changed in the lung specific cell line 4175. The possible contribution of identified proteins to differences in metastatic behavior of the cell lines is discussed.
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PMID:2-DE analysis of breast cancer cell lines 1833 and 4175 with distinct metastatic organ-specific potentials: comparison with parental cell line MDA-MB-231. 1842 82

Insulin-like growth factor II (IGFII) acts as a potent mitogen for several tumor types and has been reported to positively influence astrocytoma cell growth and motility. In the central nervous system, IGFII bioavailability is mainly modulated by insulin-like growth factor binding protein 2 (IGFBP2), which sequestrates IGFII and therefore prevents its interaction with the type-1 IGF receptor (IGF-IR). Proteolysis of IGFBP2 is the predominant mechanism recognized to reduce the binding affinity of IGFBP2 for IGFII, thus favoring dissociation of IGFII from the IGFBP2-IGFII complex. It is known that certain proteases involved in astrocytoma malignancy, such as matrix metalloproteinase-7 (MMP-7), plasmin, and cathepsin D, are able to proteolyze IGFBP2 in vitro. The present study aims to investigate whether other proteases expressed by astrocytomas, specifically MMP-2, MMP-9, and membrane-type 1 matrix metalloprotease (MT1-MMP), are able to proteolyze the IGFBP2-IGFII complex. Our results show the following: (i) MMP-9 proteolyzes the IGFBP2-IGFII complex in vitro, while MMP-2 and MT1-MMP do not; (ii) this MMP-9-induced IGFBP2-IGFII complex proteolysis releases free IGFII, which contributes to enhance the motility and the growth of LN229 astrocytoma cells. Furthermore, this study also highlights that the formation of the IGFBP2-IGFII complex inhibits IGFBP2's cell motility promoting effect by reducing the pool of free IGFBP2. In conclusion, MMP-9-induced IGFBP2 proteolysis may be regarded as an important post-translational event involved in astrocytoma aggressiveness. These new findings support drug targeting of MMP-9 as an interesting approach in the treatment of astrocytoma.
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PMID:Matrix metalloproteinase-9 interplays with the IGFBP2-IGFII complex to promote cell growth and motility in astrocytomas. 1856

Cell line models aid in understanding cancer aggressiveness. The aim of this study was the establishment of a metastatic variant (T24M) of the T24 bladder cancer cell line and its initial characterization at chromosomal and proteomic levels. T24M were spontaneously developed in mice from T24 cells, following cycles of subcutaneous injections and culture in vitro. Transwell migration assays and injections in mice revealed increased migration and tumorigenic properties of T24M compared to the T24 cells. Cytogenetic analysis demonstrated that T24M retained several karyotypic characteristics of the parental cells and also acquired novel chromosomal aberrations related to aggressive bladder cancer. Proteomic analysis of the T24 and T24M cells by 2-DE and MS led to the generation of their 2-DE proteomic map and revealed differences in multiple proteins. These include proteases of the lysosomal and proteasome degradation pathways, mitochondrial and cytoskeletal proteins. The 2-DE findings were confirmed by immunoblotting of cell lysates and immunohistochemistry of bladder cancer tissue sections for cathepsin D and activity assays for proteasome. Collectively, our results suggest that the T24M cells reflect many known chromosomal and proteomic aberrations encountered in aggressive bladder cancers but also provide access to novel findings with potentially clinical applications.
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PMID:Chromosomal and proteome analysis of a new T24-based cell line model for aggressive bladder cancer. 1910 84

To characterize proteins involved in melanoma dissemination, protein profiles from B16F10 and B16Bl6 cells were compared, as only B16Bl6 cells give pulmonary metastases after subcutaneous graft. As B16F10 and B16Bl6 cells had the same invasive capacities in vitro, we wondered whether their extracellular content could be different and correlate with their metastatic properties. We have shown that B16F10 and B16Bl6 culture cell supernatants have different modulatory effects on HT1080 fibrosarcoma cell invasion in Matrigel-coated chambers. B16Bl6 supernatants significantly enhanced HT1080 in vitro invasion as compared with B16F10 ones, suggesting differences in their protein profiles. Indeed, proteomic analysis allowed the identification of 18 differential proteins. Among the proteins with a higher concentration in B16Bl6 supernanants, lactate dehydrogenase B, M2 pyruvate kinase, cathepsin D, and galectin 1 were involved in the melanoma aggressiveness signature. Interestingly, several Gag retroviral proteins, as well as syntenin, were found mainly in the B16F10 secretome. Although its intracellular form is known as an aggressive melanoma marker, we show for the first time that syntenin was actively secreted and could reduce the invasion process, probably by protein interactions in the B16 model.
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PMID:B16 melanoma secretomes and in vitro invasiveness: syntenin as an invasion modulator. 2001 92

Lysosomal proteases are actively involved in pathogenesis of cancer progression. Alterations in proteases and their inhibitors interaction were suggested to be implicated in the processes of tumor invasion and metastasis. Among proteases connected with malignant growth, cysteine cathepsins B and L and aspartic cathepsin D play the main role in the tumor development. The present study was designed to investigate activity of cathepsins B, L and D activity in the development and treatment of murine experimental leukemias and to determine the correlation of these proteases with tumor malignancy and the chemotherapy effect. P-388 leukemia was characterized by a more aggressive development and unfavorable prognosis than L1210/1 leukemia. The activity of cathepsins B, L and D in tumor tissues of mice infected with P-388 leukemia, as well as in liver and spleen and the activity of cathepsins B and L in serum were lower than their activity in mice infected with L1210/1 leukemia. Changes of cathepsin activity in liver and spleen of mice with leukemias have demonstrated a level of aggressiveness of tumor development and invasion of liver and spleen by neoplastic cells. The treatment resulted in the increase of cathepsin B, L and D activities in tumor tissue, liver, spleen and cathepsin B and L activities in serum. The highest activity of proteases was revealed in the groups of mice characterized by the greatest suppression of tumor growth. These data have shown that lysosomal proteases are involved in progression of murine experimental leukemias and elimination of tumor cells in the result of treatment. Determination of the activity of cysteine and aspartic proteases can be used for evaluation of cancer diseases malignancy, their sensitivity for chemotherapy and efficiency of treatment.
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PMID:[The lysosomal cathepsins B, L and D in development of murine experimental leukemias]. 2001 93

Experimental models relating to human glioblastoma multiformes (hGBMs) involve the intracranial or intracerebral injection of human GBM cells into nude mice or rats. The aim of the present study was to compare a number of biological characteristics of hGBMs as opposed to experimental GBMs obtained by grafting either human U87 or U373 glioblastoma cells into the brains of nude mice. Biological assessments involve four distinct sets of parameters, i.e. i) the determination of the nuclear DNA content, ii) the determination of proliferative activity, iii) the assessment of p53 nuclear phosphoprotein immunohistochemical reactivity, and iv) the assessment of GFAP, VIM, LEU-7, S-100 and CAT D protein immunohistochemical reactivity. While most of the human glioblastoma multiformes (hGBMs) under study were immunohistochemically reactive to GFAP, S-100, LEU-7 and VIM as indeed were the experimental U373 GBMs, the U87 ones were reactive to VIM only. Furthermore, the U87 GBMs appeared to be more aggressive than the U373 ones since the former were associated with a shorter tumor-bearing mouse survival time than the latter. Such aggressiveness was further associated with a proliferative activity and a cathepsin D immunoreactivity, both of which were markedly higher in the U87 GBMs than in the U373 GBMs. These two experimental GBM models also exhibited tumors which were predominantly diploid. The present study shows that it is possible to set up experimentally in vivo models which strongly mimic human glioblastoma multiformes. Such models consist of grafting human glioblastoma cell lines, namely U87 and U373, into the brains of nude mice. However, while it is true that experimental GBMs closely resemble the hGBMs with respect to some biological characteristics, they also differ in many other significant biological characteristics.
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PMID:The characterization of nuclear-DNA content, the proliferative activity and the immunohistochemical expression of gfap, vim, leu-7, s-100, p53 and cathepsin-d in human glioblastoma multiformes (hgbms) versus human gbm cell-lines grafted into the brains of nude-mice. 2155 62

Lysosomal proteases may be involved in facilitating cancer invasion and metastatic spread by degradation of basement membranes and intercellular matrix. Overexpression of cathepsin D, a lysosomal aspartyl protease, has been reported in different tumours and seems to constitute a prognostic factor for survival in patients with breast cancer. The current study investigates immunohistochemical staining using anti-cathepsin D monoclonal antobodies (M1G8) in prostate cancer specimens and tissue from patients with benign prostatic hyperplasia (BPH). Among 41 tumours expression of cathepsin D was observed in 14 of 26 (54%) low stage and grade tumours (T-1-2/G(1-2)) and in 12 of 15 (86%) high stage and grade tumours (T-3, G(3)). Cathepsin D positivity was found within the cytoplasm and at the surface of tumour cells localized in glandular structures and in single cells invading the prostatic stroma, while no staining was observed in normal prostatic tissue and in mesenchymal cells. Two of ten specimens from patients with benign prostatic hyperplasia showed a weakly positive staining reaction within glandular structures. The clinical course of localized prostate cancer appears to be highly variable and the different treatment strategies (radical prostatectomy, radiation therapy or surveillance) have come under debate. For the determination of the biological aggressiveness of prostate cancer in the individual patient easily available biological prognostic factors are needed. This report demonstrates overexpression of cathepsin D in prostate cancer specimens with increasing frequency in patients with tumours of high grade and stage. The usefulness of cathepsin D immunohistochemistry as a prognostic factor should be prospectively evaluated.
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PMID:Immunohistochemical detection of cathepsin-d expression in prostate-cancer. 2160 25

Procathepsin D (pCD) is overexpressed and secreted by cells of various tumor types including breast and lung carcinomas, affecting multiple features of tumor cells including proliferation, invasion, metastasis and apoptosis. As more and more attention has been focused on potential use of pCD in clinical practice, we devoted this paper to summarize the three major potentials of pCD--tumor marker, potential drug and screening agent. Despite more than 20 years of studies and numerous reports of the association between pCD level and tumor size, tumor grade, tumor aggressiveness, and incidence of metastasis, pCD is still not used as a marker of cancer development. This is due to problems in distinguishing between pCD expressed by cancer derived cells and normal tissue cells and in the exact measuring of its different molecular forms (pCD, single chain cathepsin D (CD) and two chain CD) in tumor tissue. Numerous studies demonstrated that pCD secreted from cancer cells affects multiple stages of tumor progression. Subsequent data showing that inhibition of pCD secretion from cancer cells can inhibit cancer cell growth in vitro and in vivo suggested the possibility of using pCD suppression in clinical practice. A third possibility of using pCD in clinical practice is represented by the use of anti-pCD autoantibodies in screening cancer patients or in correlation with the level of these antibodies with the progress of cancer disease. Despite the fact that preliminary findings suggested such correlation, more detailed studies revealed significant setbacks.
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PMID:Procathepsin D as a tumor marker, anti-cancer drug or screening agent. 2229 75


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