Crosstalk between glucocorticoid and mineralocorticoid receptors boosts glucocorticoid-induced killing of multiple myeloma cells.
Glucocorticoid receptor
Glucocorticoids
Mineralocorticoid receptor
Multiple myeloma
Nuclear receptor crosstalk
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
14 Aug 2023
14 Aug 2023
Historique:
received:
22
05
2023
accepted:
27
07
2023
revised:
11
07
2023
medline:
15
8
2023
pubmed:
14
8
2023
entrez:
14
8
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37578563
doi: 10.1007/s00018-023-04900-x
pii: 10.1007/s00018-023-04900-x
pmc: PMC10425521
doi:
Substances chimiques
Glucocorticoids
0
Receptors, Mineralocorticoid
0
Dexamethasone
7S5I7G3JQL
Receptors, Glucocorticoid
0
Spironolactone
27O7W4T232
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
249Subventions
Organisme : Agentschap Innoveren en Ondernemen
ID : 131374
Organisme : Kom op tegen Kanker
ID : KDB 2012-VLK-GC-MM
Organisme : Kom op tegen Kanker
ID : STI.VLK.2018.0019.01
Organisme : Vlaams Instituut voor Biotechnologie
ID : Institutional funding
Organisme : Universiteit Gent
ID : Institutional funding
Informations de copyright
© 2023. The Author(s).
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