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

Abstract

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.

Editorial: Integrating transcriptional modulation in systemic tumor therapy

“…Nuclear receptor agonists' context-dependent activity profiles, theme-dependent interactions with one another, and often poor monoactivity are reasons for their hesitant combinatorial application in oncology (2,3). Harrer et al present novel therapy approaches unlocking the phenotypic plasticity of tumors as the basis for the comprehensive implementation of nuclear receptor agonists in tumor therapy (4,5).…”

“…Nuclear receptor agonists’ context-dependent activity profiles, theme-dependent interactions with one another, and often poor monoactivity are reasons for their hesitant combinatorial application in oncology ( 2 , 3 ). Harrer et al.…”

Novel Evolution of the Mineralocorticoid Receptor in Humans compared to Chimpanzees, Gorillas and Orangutans

“…These three human cortisol, and other corticosteroids. We also will screen MR-GR dimers for activation by aldosterone and other corticosteroids [28,[42][43][44][45]49], which is an important mechanism for regulating corticosteroid activity in the brain [15,17,44,50,51].…”

“…All four chimpanzee MRs contain (Ile-180, Val-241) in their NTD, which is similar to the NTD in one human MR (Figure 2 cortisol, and other corticosteroids. We also will screen dimers of these MRs with the GR for activation by aldosterone and other corticosteroids [28,[42][43][44][45]49], which is an important mechanism for regulating corticosteroid activity in the brain [15,17,44,50,51].…”

Lysine-Cysteine-Serine-Tryptophan Inserted into the DNA-Binding Domain of Human Mineralocorticoid Receptor Increases Transcriptional Activation by Aldosterone

“…We propose that MRs with (Ile-180, Ala-241) or (Val-180, Val-241) in their NTD evolved in humans after their divergence from chimpanzees. In the light of the diverse physiological functions of the MR in humans in regulating transcription in kidney, brain, heart, skin, lungs and other tissues[11,[13][14][15][16][17][18][19][20][21][22]48], the evolution of human MRs with (Ile-180, Ala-241) or (Val-180, Val-241) in their NTD may have been important in the evolution of humans from chimpanzees[41].The interaction of the MR with the GR to form heterodimers is important[49][50][51][52][53][54][55]. The response to aldosterone and other corticosteroids to heterodimers of human MRs containing KCSW in the DBD, as well as either (Ile-180, Ala-241), (Ile-180, Val-241) or (Val-180, Val-241) in the NTD with human GR needs to be explored.…”