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PXD043635

PXD043635 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleCrosstalk between the glucocorticoid and mineralocorticoid receptor boosts glucocorticoid-induced killing of multiple myeloma cells
DescriptionThe 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’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates 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, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising 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 but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses 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 patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.
HostingRepositoryPRIDE
AnnounceDate2023-11-14
AnnouncementXMLSubmission_2023-11-14_09:12:34.238.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterLiesbeth Hoekman
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Exploris 480
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-07-10 00:34:35ID requested
12023-10-24 14:48:52announced
22023-11-14 09:12:43announced2023-11-14: Updated project metadata.
Publication List
Clarisse D, Prekovic S, Vlummens P, Staessens E, Van Wesemael K, Thommis J, Fijalkowska D, Acke G, Zwart W, Beck IM, Offner F, De Bosscher K, Crosstalk between glucocorticoid and mineralocorticoid receptors boosts glucocorticoid-induced killing of multiple myeloma cells. Cell Mol Life Sci, 80(9):249(2023) [pubmed]
Keyword List
submitter keyword: glucocorticoid receptor
GR
LC-msms
mineralocorticoid receptor
MR
myeloma
Dexamethasone
Spironolacton
c-myc;
Contact List
Onno Bleijerveld
contact affiliationProteomics Facility, Netherlands Cancer Institute, Amsterdam, Netherlands.
contact emailO.bleijerveld@nki.nl
lab head
Liesbeth Hoekman
contact affiliationThe Netherlands Cancer Institute, Amsterdam, The Netherlands.
contact emaill.hoekman@nki.nl
dataset submitter
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Dataset FTP location
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PRIDE project URI
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