Glucocorticoid receptor expression in multiple myeloma patients is a predictor of survival

Pozhitkov, Alex; Rosenzweig, Michael; Pichiorri, Flavia; Gunes, Emine Gulsen; Buettner, Ralf; Rosen, Steven T.

doi:10.1080/10428194.2020.1811860

Cited by 5 publications

(3 citation statements)

References 17 publications

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“…4 O, P). For GR, this contrasts a previous study, where high expression levels at diagnosis were found predictive for OS [ 63 ]. One reason for this difference may be that Rosen and colleagues stratified patients in two subgroups, based on whether they underwent stem cell transplantation or not, and another reason may be that at that time only version IA13 of the database was available (with 650 patients vs. IA14 with 750 patients).…”

Section: Discussioncontrasting

confidence: 99%

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

Clarisse,

Prekovic,

Vlummens

et al. 2023

Cell. Mol. Life Sci.

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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.

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Section: Discussioncontrasting

confidence: 99%

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

Clarisse,

Prekovic,

Vlummens

et al. 2023

Cell. Mol. Life Sci.

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“…It has reported that GR expression is a major mechanism of Dex resistance and is associated with better patient outcome in MM [3,13,15]. Consistent with previous studies, we found that GR expression showed negative correlation with Dex IC 50 values in primary MM cells (n=15) (Figure 3A).…”

Section: Sumoylation Inhibition Enhances Dex Sensitivity By Upregulating Gr Through Downregulating Mir-130bsupporting

confidence: 91%

“…Expression of SUMO E1 is upregulated in Multiple Myeloma and associated with poor prognosis mRNA pro ling of myeloma patient cohort GSE5900 showed that SUMO E1 (Ubiquitin Like Modi er Activating Enzyme 2(UBA2)/SUMO activating enzyme 2 (SAE2)) gene expression was signi cantly upregulated at the premalignant myeloma stage (MGUS) and in the asymptomatic myeloma phase (smoldering MM) compared to healthy plasma cells (supplemental Figure S1A). Moreover, higher SUMO E1 (UBA2) gene expression in MM plasma cells was associated with signi cantly shorter survival in both GSE2658 (n=559) and CoMMpass (clinical trial NCT01454297, n=764) database (Supplemental Figure S1B&C) [12,13]. These data suggest that SAE2 might be associated with therapy resistance in MM.…”

Section: Resultsmentioning

confidence: 90%

SUMOylation Inhibition Enhances Dexamethasone Sensitivity in Multiple Myeloma

Liu

Aldana-Masangkay

et al. 2021

Preprint

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BackgroundMultiple myeloma (MM) is an incurable plasma cell malignancy. Although Dexamethasone (Dex) is the most widely used therapeutic drug in MM treatment, patients develop Dex resistance leading to progressive disease, demanding an urgent need to investigate the mechanisms driving Dex resistance and develop new reagents to address this problem. We propose SUMOylation as a potential mechanism regulating Dex resistance and SUMOylation inhibition can enhance Dex sensitivity in MM.MethodsUsing MM cell lines and primary MM samples from relapsing MM patients, we evaluated the effects of knockdown of SUMO E1 (SAE2) or using TAK-981, a novel and specific SUMO E1 inhibitor, on Dex sensitivity. Xenograft mouse models were generated to determine the in vivo anti-MM effects of TAK-981 as a single agent and in combination with Dex. miRNA-seq, RNA-seq and GSEA analysis were utilized for evaluating key factors mediating Dex resistance. Chromatin immunoprecipitation (ChIP) assay was performed to determine the binding occupancy of c-Myc on promoter region of miRs. ResultsWe observed a significant negative correlation between SUMO E1 (SAE2) expression and Dex sensitivity in primary MM samples. Knockdown of SAE2 or using TAK-981 significantly enhances myeloma sensitivity to Dex in MM cell lines. Moreover, the enhanced anti-MM activity by TAK-981 and Dex combination has been validated using primary relapsing MM patient samples and xenograft mouse models. SUMOylation inhibition increased glucocorticoid receptor (GR) expression via downregulation miR-130b. Using RNA and microRNA sequencing, we identified miR-551b and miR-25 as important miRs mediating Dex resistance in MM. Overexpression of miR-551b and miR-25 caused resistance to Dex, however, knockdown of miR-551b and miR-25 significantly enhanced Dex sensitivity in MM. SAE2 knockdown or TAK-981 treatment downregulated the expression of miR-551b and miR-25, leading to induction of miR targets ZFP36, ULK1 and p27, resulting in apoptosis and autophagy. We demonstrated c-Myc as a major transcriptional activator of miR-130b, miR-551b and miR-25 and SUMOylation inhibition downregulates these miRs level by decreasing c-Myc level. ConclusionOur study proves SUMOylation plays a crucial role in Dex resistance in MM and SUMOylation inhibition appears to be an attractive strategy to advance to the clinic for MM patients.

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Effects of Exercise Rehabilitation on Physical Function in Adults With Hematological Cancer Receiving Active Treatment: A Systematic Review and Meta-Analysis

Moore,

Northey,

Crispin

et al. 2023

Seminars in Oncology Nursing

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Glucocorticoid receptor expression in multiple myeloma patients is a predictor of survival

Cited by 5 publications

References 17 publications

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

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

SUMOylation Inhibition Enhances Dexamethasone Sensitivity in Multiple Myeloma

Effects of Exercise Rehabilitation on Physical Function in Adults With Hematological Cancer Receiving Active Treatment: A Systematic Review and Meta-Analysis

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