PSMB7 is associated with anthracycline resistance and is a prognostic biomarker in breast cancer
ABSTRACT To date individual markers have failed to correctly predict resistance against anticancer agents in breast cancer. We used gene expression patterns attributable to chemotherapy-resistant cells to detect potential new biomarkers related to anthracycline resistance. One of the genes, PSMB7, was selected for further functional studies and clinical validation.
We contrasted the expression profiles of four pairs of different human tumour cell lines and of their counterparts resistant to doxorubicin. Observed overexpression of PSMB7 in resistant cell lines was validated by immunohistochemistry. To examine its function in chemoresistance, we silenced the gene by RNA interference (RNAi) in doxorubicin-resistant MCF-7 breast cancer cells, then cell vitality was measured after doxorubicin treatment. Microarray gene expression from GEO raw microarray samples with available progression-free survival data was downloaded, and expression of PSMB7 was used for grouping samples.
After doxorubicin treatment, 79.8+/-13.3% of resistant cells survived. Silencing of PSMB7 in resistant cells decreased survival to 31.8+/-6.4% (P>0.001). A similar effect was observed after paclitaxel treatment. In 1592 microarray samples, the patients with high PSMB7 expression had a significantly shorter survival than the patients with low expression (P<0.001).
Our findings suggest that high PSMB7 expression is an unfavourable prognostic marker in breast cancer.
Full-textDOI: · Available from: Balázs Györffy, Mar 31, 2015
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ABSTRACT: Deltamethrin (DM) insecticides are currently being promoted worldwide for mosquito control, because of the high efficacy, low mammalian toxicity and less environmental impact. Widespread and improper use of insecticides induced resistance, which has become a major obstacle for the insect-borne disease management. Resistance development is a complex and dynamic process involving many genes. To better understand the possible molecular mechanisms involved in DM resistance, a proteomic approach was employed for screening of differentially expressed proteins in DM-susceptible and -resistant mosquito cells. Twenty-seven differentially expressed proteins were identified by two-dimensional electrophoresis (2-DE) and mass spectrometry (MS). Four members of the ubiquitin-proteasome system were significantly elevated in DM-resistant cells, suggesting that the ubiquitin-proteasome pathway may play an important role in DM resistance. Proteasome subunit beta type 6 (PSMB6) is a member of 20S proteasomal subunit family, which forms the proteolytic core of 26S proteasome. We used pharmaceutical inhibitor and molecular approaches to study the contributions of PSMB6 in DM resistance: the proteasome inhibitor MG-132 and bortezomib were used to suppress the proteasomal activity and siRNA was designed to block the function of PSMB6. The results revealed that both MG-132 and bortezomib increased the susceptibility in DM-resistant cells and resistance larvae. Moreover, PSMB6 knockdown decreased cellular viability under DM treatment. Taken together, our study indicated that PSMB6 is associated with DM resistance in mosquitoes and that proteasome inhibitors such as MG-132 or bortezomib are suitable for use as a DM synergist for vector control.PLoS ONE 06/2013; 8(6):e65859. DOI:10.1371/journal.pone.0065859 · 3.53 Impact Factor
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ABSTRACT: The chemotherapy combined with gene therapy has received great attention. We developed targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab' co-delivering adriamycin (ADR) and ribonucleotide reductase M2 (RRM2) siRNA (ADR-RRM2-TLPD), to achieve combined therapeutic effects in human hepatocellular carcinoma (HCC) overexpressing EGFR. The antitumor activity and mechanisms of ADR-RRM2-TLPD were investigated. The results showed that RRM2 expression was higher in HCC than in non-HCC tissue, and RRM2 siRNA inhibited HCC cell proliferation, suggesting that RRM2 is a candidate target for HCC therapy. ADR-RRM2-TLPD delivered ADR and RRM2 siRNA to EGFR overexpressing HCC cells specifically and efficiently both in vitro and in vivo, resulting in enhanced therapeutic effects (cytotoxicity, apoptosis and senescence-inducing activity) compared with single-drug loaded or non-targeted controls, including ADR-NC-TLPD (targeted LPD co-delivering ADR and negative control siRNA), RRM2-TLPD (targeted LPD delivering RRM2 siRNA) and ADR-RRM2-NTLPD (non-targeted LPD co-delivering ADR and RRM2 siRNA). Mechanism studies showed that p21 is involved in the combined therapeutic effect of ADR-RRM2-TLPD. The average weight of the orthotopic HCC in mice treated with ADR-RRM2-TLPD was significantly lighter than that of mice treated with other controls. Thus, ADR-RRM2-TLPD represents a potential strategy for combined therapy of HCC overexpressing EGFR.Biomaterials 09/2013; 34(38). DOI:10.1016/j.biomaterials.2013.08.088 · 8.31 Impact Factor
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ABSTRACT: To investigate the role of RAD001 in the reversing of drug resistance of SGC7901/DDP, we cultured SGC7901/DDP cells with different groups of drugs (RAD001, cisplatin (DDP) alone, or the combination of RAD001 and DDP); after that, we detected the drug sensitivity, cell apoptosis, and levels of P-gp, MRP1, and survivin in the cells of SGC7901/DDP by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphe-nyltetrazolium bromide) assay, flow cytometry, immunohistochemical analysis, and Western blot analysis. There was no significant difference between DDP 2.5-mg/L group and negative control group. When the cells were pretreated with RAD001 2.5, 5 nmol/L, the proliferation of SGC7901/DDP cells was inhibited by DDP 2.5 mg/L significantly, compared to negative control group, DDP 2.5-mg/L group, and RAD001 2.5, 5-nmol/L group, respectively (P < 0.05); there were significant differences between combination groups (P < 0.05). DDP 2.5 mg/L and RAD001 2.5 nmol/L did not induce apoptosis of SGC7901/DDP cells alone (P > 0.05). When SGC7901/DDP cells were pretreated with RAD001 2.5 nmol/L, DDP 2.5 mg/L increased the apoptosis rate significantly compared to groups of control and DDP 2.5 mg/L alone (P < 0.05). Immunohistochemical staining (Table 5, Fig. 2) and Western blot analysis (Fig. 3) indicated that when SGC7901/DDP cells were pretreated with RAD001 2.5 nmol/L, the expression of P-gp, MRP1, and survivin decreased by different degrees. Our results have confirmed that RAD001 in combination with DDP could overcome chemoresistance of SGC7901/DDP cells by decreasing the levels of P-gp, MRP1, and survivin through the mTOR pathway.Tumor Biology 06/2014; 35(9). DOI:10.1007/s13277-014-1719-1 · 2.84 Impact Factor