Crosstalk between glucocorticoid and mineralocorticoid receptors boosts glucocorticoid-induced killing of multiple myeloma cells.

Autor: Clarisse D; VIB Center for Medical Biotechnology, Technologiepark-Zwijnaarde 75, 9052, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Prekovic S; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands., Vlummens P; Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium., Staessens E; VIB Center for Medical Biotechnology, Technologiepark-Zwijnaarde 75, 9052, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium., Van Wesemael K; VIB Center for Medical Biotechnology, Technologiepark-Zwijnaarde 75, 9052, Ghent, Belgium.; Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium., Thommis J; VIB Center for Medical Biotechnology, Technologiepark-Zwijnaarde 75, 9052, Ghent, Belgium.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium., Fijalkowska D; VIB Center for Medical Biotechnology, Technologiepark-Zwijnaarde 75, 9052, Ghent, Belgium., Acke G; Department of Chemistry, Ghent University, Ghent, Belgium., Zwart W; Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Beck IM; Department of Health Sciences, Odisee University of Applied Sciences, Ghent, Belgium., Offner F; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.; Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium., De Bosscher K; VIB Center for Medical Biotechnology, Technologiepark-Zwijnaarde 75, 9052, Ghent, Belgium. karolien.debosscher@vib-ugent.be.; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. karolien.debosscher@vib-ugent.be.; Cancer Research Institute Ghent (CRIG), Ghent, Belgium. karolien.debosscher@vib-ugent.be.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2023 Aug 14; Vol. 80 (9), pp. 249. Date of Electronic Publication: 2023 Aug 14.
DOI: 10.1007/s00018-023-04900-x
Abstrakt: The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR action in myeloma. Here, we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that plays a role in improved myeloma cell killing. We show that the GR agonist dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells. In a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk likely arises from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR-MR homodimerization, while leaving GR-GR homodimerization intact. Unbiased transcriptomics analyses reveal that c-myc and many of its target genes are downregulated most by combined Dex-Spi treatment. Proteomics analyses further identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex-Spi downregulated genes and proteins that may predict prognosis in the CoMMpass myeloma patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies for glucocorticoid-based dose-reduction.
(© 2023. The Author(s).)
Databáze: MEDLINE
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