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Updated: Jul 10, 2026
An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Proteomic evaluation of pathways associated with dexamethasone-mediated apoptosis and resistance in multiple myeloma
Karen S Rees-Unwin1, Rachel A Craven, Emma Davenport
1Academic Unit of Haematology and Oncology, School of Medicine, Algernon Firth Building, University of Leeds, Leeds, UK.
Abstract:
We have used global protein expression analysis to characterize the pathways of dexamethasone-mediated apoptosis and resistance in myeloma. Analysis of MM.1S cells by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) identified a series of proteins that were up- and downregulated following dexamethasone treatment. Downregulated proteins included proteins involved in cell survival and proliferation, whereas upregulated proteins were involved in post-translational modification, protein folding and trafficking. A comparison with published gene expression studies identified FK binding protein 5 (FKBP5) (also known as FKBP51), a key regulatory component of the Hsp90-steroid-receptor complex to be increased at the mRNA and protein level postdexamethasone exposure. Quantitative real time polymerase chain reaction and 2D-PAGE analysis of the dexamethasone resistant cell line MM.1R demonstrated no increase in FKBP5, consistent with its association with dexamethasone-mediated apoptosis. Western blot analysis of FKBP5 and other members of the Hsp90-receptor complex showed an increase in FKBP5 whilst FKBP4 (also known as FKBP52) and Hsp90 expression remained constant. No changes were observed in MM.1R. In conclusion, we demonstrated that following steroid receptor signalling, the cell carries out a number of adaptive responses prior to cell death. Interfering with these adaptive responses may enhance the myeloma killing effect of dexamethasone.
Insights
Dexamethasone triggers adaptive responses in myeloma cells before apoptosis. Upregulation of FK binding protein 5 (FKBP5) is linked to cell death, suggesting therapeutic targets for enhancing dexamethasone efficacy.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Dexamethasone is a corticosteroid used in multiple myeloma treatment.
- Understanding dexamethasone's mechanism of action in apoptosis and resistance is crucial for improving therapy.
- Cellular adaptive responses to steroid signaling influence treatment outcomes.
Purpose of the Study:
- To characterize protein expression changes during dexamethasone-induced apoptosis and resistance in myeloma.
- To identify key proteins involved in dexamethasone's effects on myeloma cells.
- To explore potential strategies for enhancing dexamethasone's anti-myeloma activity.
Main Methods:
- Global protein expression analysis using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE).
- Quantitative real-time polymerase chain reaction (qRT-PCR) for gene expression analysis.
- Western blot analysis for specific protein quantification.
Main Results:
- Dexamethasone treatment altered the expression of numerous proteins in MM.1S myeloma cells.
- Upregulated proteins were associated with post-translational modification, protein folding, and trafficking.
- FK binding protein 5 (FKBP5) expression increased at mRNA and protein levels in sensitive cells but not in resistant cells (MM.1R).
- FKBP5 upregulation correlated with dexamethasone-mediated apoptosis, while FKBP4 and Hsp90 levels remained constant.
Conclusions:
- Myeloma cells undergo adaptive responses following steroid receptor signaling before initiating apoptosis.
- FKBP5 is a key regulator in dexamethasone-induced apoptosis, its increase being associated with cell death.
- Targeting these adaptive responses could potentially enhance the efficacy of dexamethasone in treating multiple myeloma.
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