Circulating 20S proteasome in patients with non-metastasized breast cancer
Clinic of Obstetrics and Gynecology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, D-45147 Essen, Germany. Anticancer research
(Impact Factor: 1.83).
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.
Available from: Ceyda Acilan
- "In fact, Hoffmann et al. recently showed that circulating proteasome concentrations were significantly higher in primary breast cancer patients than in healthy controls. They therefore concluded that the ubiquitin–proteasome system might represent a potential target in breast cancer treatment . The activity of the proteasome as well as the levels of the proteasome subunits were also increased in at least 90% of the primary breast cancer tissue specimens; whereas, no significant increases in the proteasome activity or the levels of its subunits were observed in benign breast tumors . "
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The 26S proteasome is a proteolytic enzyme found in both cytoplasm and nucleus. In this study, we examined the differential expression of proteasome inhibitor bortezomib-induced proteins in p53-deficient 4T1 cells. It was found that GRP78 and TCEB2 were over-expressed in response to treatment with bortezomib for 24h. Next, we analyzed the expression of intracellular proteins in response to treatment with 100nM bortezomib for 24h by label-free LC-MS/MS. These analyses showed that Hsp70, the 26S proteasome non-ATPase regulatory subunit 14 and sequestosome 1 were increased at least 2 fold in p53-deficient 4T1 cells. The proteins identified by label-free LC-MS/MS were then analyzed by Ingenuity Pathway Analysis (IPA) Tool to determine biological networks affected by inhibition of the 26S proteasome. The analysis results showed that post-translational modifications, protein folding, DNA replication, energy production and nucleic acid metabolism were found to be among the top functions affected by the 26S proteasome inhibition. The biological network analysis indicated that ubiquitin may be the central regulator of the pathways modulated after bortezomib-treatment. Further investigation of the mechanism of the proteins modulated in response to the proteasomal inhibition may lead to the design of more effective and novel therapeutic strategies for cancer.
Although the proteasome inhibitor bortezomib is approved and used for the treatment of human cancer (multiple myeloma), the mechanism of action is not entirely understood. A number of studies showed that proteasome inhibitors induced apoptosis through upregulation of tumor suppressor protein p53. However, the role of tumor suppressor protein p53 in bortezomib-induced apoptosis is controversial and not well-understood. The tumor suppressor p53 is mutated in at least 50% of human cancers and is strongly induced by proteasomal inhibition. Some also reported that the proteasome inhibitor can induce apoptosis in a p53-independent manner. Also, it is reported that Noxa, a target of p53, is induced in response to proteasomal inhibition in a p53-independent manner. However, we have also previously reported that neither Puma nor Noxa are induced by proteasomal inhibition in p53-null 4T1 breast cancer cells, which is commonly used for in vivo breast cancer tumor models. The current results provided additional targets of proteasome inhibitor bortezomib and may therefore help in understanding the p53-independent mechanism of apoptosis induction by proteasome inhibitors. In addition, the results presented in this current study report for the first time that proteasomal subunit Psmd14, anti-apoptotic GRP78, anti apoptotic protein Card10, Dffb, Traf3 and Trp53bp2 are regulated and overexpressed in response to proteasome inhibitor bortezomib in p53-deficient 4T1 cells. Therefore, novel therapeutic strategies targeting these anti-apoptotic or pro-apoptotic proteins as well as inhibiting the proteasome simultaneously may be more effective against cancer cells. The proteins identified here present new avenues for the development of anti-cancer drugs.
Journal of Proteomics 10/2014; DOI:10.1016/j.jprot.2014.09.010 · 3.89 Impact Factor
Available from: Tobias Klatte
- "In malignant melanoma, a similar relationship was observed (Stoebner et al, 2005). However, immunohistochemical expression in the tumour did not correlate with circulating proteasome levels in several studies (Heubner et al, 2011; Hoffmann et al, 2011), indicating a role of non-malignant cells and benign diseases. "
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ABSTRACT: To date, no reliable serum marker for clear cell renal cell carcinoma (CCRCC) is available. The aim of this study was to evaluate the putative significance of circulating 20S proteasome levels.
Preoperative 20S proteasome serum levels were determined in 113 CCRCC patients and 15 healthy controls by a sandwich enzyme-linked immunosorbent assay. Associations with CCRCC, pathological variables, disease-specific survival (DSS), and response to sunitinib were evaluated.
Median 20S proteasome levels were higher in CCRCC patients than in healthy controls (4.66 vs 1.52 μg ml(-1), P<0.0001). The area under the receiver operating characteristics curve curve was 87.1%. The 20S proteasome levels were associated with symptoms (P=0.0008), distant metastases (P=0.0011), grade (P=0.0247), and necrosis (P=0.0462). The 20S proteasome levels were identified as a prognostic factor for DSS in both univariable (hazards ratio 1.21, P<0.001) and multivariable (hazards ratio 1.17, P=0.0015) survival analysis. In patients responding to sunitinib, 20S proteasome levels were lower than in patients with stable disease and progressive disease.
This study demonstrates for the first time that increased 20S proteasome levels are associated with CCRCC, advanced disease, and poor prognosis. Routine use of this marker may allow better diagnosis, risk stratification, risk-adjusted follow-up, and identification of patients with a greater likelihood of response to targeted therapy.
British Journal of Cancer 02/2012; 106(5):904-8. DOI:10.1038/bjc.2012.20 · 4.84 Impact Factor
Available from: Ingrid Fruitier-Arnaudin
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ABSTRACT: Hemorphin peptides exhibit biological activities that interfere with the endorphin system, the inflammatory response, and blood-pressure control. VV-hemorphin-7 and LVV-hemorphin-7 peptides exert a hypotensive effect, in particular, by inhibiting the renin–angiotensin system. Furthermore, levels of circulating hemorphin-7 peptides have been found to be decreased in diseases such as type 1 and type 2 diabetes.
Because type 2 diabetes and obesity share common features, such as insulin resistance, microinflammation, high glomerular-filtration rate (GFR), and cardiovascular risk, we evaluated serum VV-hemorphin-7 like immunoreactivity (VVH7-i.r.) levels, using an enzyme-linked immunosorbent assay method, on a group of 54 obese subjects without diabetes or hypertension, compared with a group of 33 healthy normal-weight subjects.
Circulating VVH7-i.r. levels were significantly decreased in the obese group compared with the control group (1.98 ± 0.19 vs. 4.86 ± 0.54 µmol/l, respectively, P < 0.01), and a significant negative correlation between VVH7-i.r. and diastolic blood pressure (DBP) was found in obese patients (r = −0.35, P = 0.011). There was no significant correlation between VVH7-i.r. level and insulin resistance, metabolic syndrome, or GFR.
The decreased serum hemorphin-7 found in obese subjects, as in diabetes, may contribute to the development of hypertension and to the cardiovascular risk associated with these metabolic diseases.
Obesity 07/2012; 21(2). DOI:10.1038/oby.2012.186 · 3.73 Impact Factor
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