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Molecular responses to therapeutic proteasome inhibitors in multiple myeloma patients are donor-, cell type- and drug-dependent.

ABSTRACT: Proteasome is central to proteostasis network functionality and its over-activation represents a hallmark of advanced tumors; thus, its selective inhibition provides a strategy for the development of novel antitumor therapies. In support, proteasome inhibitors, e.g. Bortezomib or Carfilzomib have demonstrated clinical efficacy against hematological cancers. Herein, we studied proteasome regulation in peripheral blood mononuclear cells and erythrocytes isolated from healthy donors or from Multiple Myeloma patients treated with Bortezomib or Carfilzomib. In healthy donors we found that peripheral blood mononuclear cells express higher, as compared to erythrocytes, basal proteasome activities, as well as that proteasome activities decline during aging. Studies in cells isolated from Multiple Myeloma patients treated with proteasome inhibitors revealed that in most (but, interestingly enough, not all) patients, proteasome activities decline in both cell types during therapy. In peripheral blood mononuclear cells, most proteostatic genes expression patterns showed a positive correlation during therapy indicating that proteostasis network modules likely respond to proteasome inhibition as a functional unit. Finally, the expression levels of antioxidant, chaperone and aggresomes removal/autophagy genes were found to inversely associate with patients' survival. Our studies will support a more personalized therapeutic approach in hematological malignancies treated with proteasome inhibitors.

SUBMITTER: Papanagnou ED

PROVIDER: S-EPMC5915155 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Molecular responses to therapeutic proteasome inhibitors in multiple myeloma patients are donor-, cell type- and drug-dependent.

Papanagnou Eleni-Dimitra ED Terpos Evangelos E Kastritis Efstathios E Papassideri Issidora S IS Tsitsilonis Ourania E OE Dimopoulos Meletios A MA Trougakos Ioannis P IP

Oncotarget 20180403 25

Proteasome is central to proteostasis network functionality and its over-activation represents a hallmark of advanced tumors; thus, its selective inhibition provides a strategy for the development of novel antitumor therapies. In support, proteasome inhibitors, e.g. Bortezomib or Carfilzomib have demonstrated clinical efficacy against hematological cancers. Herein, we studied proteasome regulation in peripheral blood mononuclear cells and erythrocytes isolated from healthy donors or from Multipl ...[more]

PMID: 29707147

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Project description:BackgroundMultiple myeloma (MM) patients with t(14;20) have a poor prognosis and their outcome has not improved following the introduction of bortezomib (Bzb). The mechanism underlying the resistance to proteasome inhibitors (PIs) for this subset of patients is unknown.MethodsIC50 of Bzb and carfilzomib (CFZ) in human myeloma cell lines (HMCLs) were established by MTT assay. Gene Expression profile (GEP) analysis was used to determine gene expression in primary myeloma cells. Immunoblotting analysis was performed for MAFb and caspase family proteins. Immunofluorescence staining was used to detect the location of MAFb protein in MM cells. Lentiviral infections were used to knock-down MAFb expression in two lines. Apoptosis detection by flow cytometry and western blot analysis was performed to determine the molecular mechanism MAFb confers resistance to proteasome inhibitors.ResultsWe found high levels of MAFb protein in cell lines with t(14;20), in one line with t(6;20), in one with Igλ insertion into MAFb locus, and in primary plasma cells from MM patients with t(14;20). High MAFb protein levels correlated with higher IC50s of PIs in MM cells. Inhibition of GSK3β activity or treatment with Bzb or CFZ prevented MAFb protein degradation without affecting the corresponding mRNA level indicating a role for GSK3 and proteasome inhibitors in regulation of MAFb stability. Silencing MAFb restored sensitivity to Bzb and CFZ, and enhanced PIs-induced apoptosis and activation of caspase-3, - 8, - 9, PARP and lamin A/C suggesting that high expression of MAFb protein leads to insensitivity to proteasome inhibitors.ConclusionThese results highlight the role of post-translational modification of MAFb in maintaining its protein level, and identify a mechanism by which proteasome inhibitors induced stabilization of MAFb confers resistance to proteasome inhibitors, and provide a rationale for the development of targeted therapeutic strategies for this subset of patients.

Dataset Information

Molecular responses to therapeutic proteasome inhibitors in multiple myeloma patients are donor-, cell type- and drug-dependent.

Publications

Molecular responses to therapeutic proteasome inhibitors in multiple myeloma patients are donor-, cell type- and drug-dependent.

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