Circulating 20S proteasome in patients with non-metastasized breast cancer.
ABSTRACT Recent data suggest a role of the ubiquitin-proteasome system in various malignancies. In patients with neoplasms, increased extracellular concentrations of circulating 20S proteasome (c-proteasome) have been detected in blood plasma. We tested the hypothesis that the plasma c-proteasome concentration is a biomarker associated with tumor stage and nodal status in patients with the primary diagnosis of non-metastatic breast cancer.
Venous plasma concentration of 20S proteasome was measured by ELISA technique in 224 non-metastatic breast cancer patients and in 50 healthy volunteers. To assess the relation of proteasome expression to c-proteasome concentration, tumor specimens from 32 patients were immunohistochemically stained for 20S proteasome using an antibody directed against the core subunits of the catalytic domain of the 20S proteasome.
The median c-proteasome concentration was higher (p<0.0001) in breast cancer patients (397.5 ng/ml, range: 200-50,000 ng/ml) than in healthy controls (305 ng/ml, range: 140-425 ng/ml). There was no significant correlation between c-proteasome concentration and strength of proteasomal staining in tumor specimens. Neither tumor size, nor nodal status, nor any other prognostically important clinical parameter, including the presence of disseminated tumor cells in the bone marrow, correlated with high c-proteasome concentrations.
Circulating proteasome concentrations appear to be higher in patients presenting with primary breast cancer than in healthy controls. Thus, the ubiquitin-proteasome system might represent a potential target in breast cancer treatment.
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ABSTRACT: In order to determine the networks and biological functions associated with the identified proteins that were differentially expressed in response to 100 nM bortezomib treatment, the data were further analyzed using the Ingenuity Pathway Analysis (IPA) software. Bortezomib-mediated inhibition of the proteasome affected changes in the expression of proteins involved in post-translational modification, protein folding, DNA replication/repair/recombination, energy production and nucleic acid metabolism using IPA software. The merged network showed that ubiquitin (UBC gene encoding polyubiquitin-C, a precursor of ubiquitin protein) interacts with almost all proteins in the network. Interestingly, the proteasomal subunit Psmd14, a critical subunit for the development of stem cells as well, is found to be in direct contact with heat shock 70 kDa protein 1B, heat shock cognate 71 kDa, Psmc3 (a proteasomal subunit involved in diseases of meningitis and HIV-1) and also ubiquitin.Journal of Proteomics 10/2014; DOI:10.1016/j.jprot.2014.09.010 · 3.93 Impact Factor
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ABSTRACT: The ubiquitin-proteasome pathway is implicated in the pathogenesis of many haematologic malignancies, including multiple myeloma. Under conditions of rapid cell turnover and growth rate, proteasomes are returned into circulation. The measurement of their levels or activity could offer a new approach to diagnosis, prognosis and monitoring of anticancer treatment in carcinoma patients. We analysed proteasome concentration and chymotrypsin-like (ChT-L) activity in the plasma of 64 patients with a newly diagnosed multiple myeloma and 30 healthy volunteers. The values were found to be significantly higher in the studied patients and advanced disease stages compared to the control group, and decreased significant after chemotherapy. Both proteasome concentration and ChT-L activity correlated with adverse prognostic factors, such as lactate dehydrogenase and β2-macroglobulin. We also showed that proteasome concentration positively correlates with IL-6 level, as opposed to proteasome ChT-L activity. Of note, higher proteasome ChT-L activity, unlike the concentration, was proved to be an indicator of a shorter progression free survival, constituting thereby an important prognostic marker.Leukemia Research 08/2014; 38(8). DOI:10.1016/j.leukres.2014.05.008 · 2.69 Impact Factor
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ABSTRACT: Proteome quality control (PQC) is critical for the maintenance of cellular functionality and it is assured by the curating activity of the proteostasis network (PN). PN is constituted of several complex protein machines that under conditions of proteome instability aim to, firstly identify, and then, either rescue or degrade nonnative polypeptides. Central to the PN functionality is the ubiquitin-proteasome system (UPS) which is composed from the ubiquitin-conjugating enzymes and the proteasome; the latter is a sophisticated multi-subunit molecular machine that functions in a bimodal way as it degrades both short-lived ubiquitinated normal proteins and nonfunctional polypeptides. UPS is also involved in PQC of the nucleus, the endoplasmic reticulum and the mitochondria and it also interacts with the other main cellular degradation axis, namely the autophagy-lysosome system. UPS functionality is optimum in the young organism but it is gradually compromised during aging resulting in increasing proteotoxic stress; these effects correlate not only with aging but also with most age-related diseases. Herein, we present a synopsis of the UPS components and of their functional alterations during cellular senescence or in vivo aging. We propose that mild UPS activation in the young organism will, likely, promote antiaging effects and/or suppress age-related diseases. Copyright © 2015 Elsevier Inc. All rights reserved.International review of cell and molecular biology 01/2015; 314:171-237. DOI:10.1016/bs.ircmb.2014.09.002 · 4.52 Impact Factor