Abstract
Glucocorticoids (GCs) selectively trigger cell death in the multiple myeloma cell line MM1S which express NR3C1/Glucocorticoid Receptor (GR) protein, but fail to kill MM1R cells which lack GR protein. Given recent demonstrations of altered microRNA profiles in a diverse range of haematological malignancies and drug resistance, we characterized GC inducible mRNA and microRNA transcription profiles in GC sensitive MM1S as compared to GC resistant MM1R cells. Transcriptome analysis revealed that GCs regulate expression of multiple genes involved in cell cycle control, cell organization, cell death and immunological disease in MM1S cells, which remain unaffected in MM1R cells. With respect to microRNAs, mir-150-5p was identified as the most time persistent GC regulated microRNA, out of 5 QPCR validated microRNAs (mir-26b, mir-125a-5p, mir-146-5p, mir-150-5p, and mir-184), which are GC inducible in MM1S but not in MM1R cells. Functional studies further revealed that ectopic transfection of a synthetic mir-150-5p mimics GR dependent gene expression changes involved in cell death and cell proliferation pathways. Remarkably, despite the gene expression changes observed, overexpression of mir-150-5p in absence of GCs did not trigger significant cytotoxicity in MM1S or MM1R cells. This suggests the requirement of additional steps in GC induced cell death, which can not be mimicked by mir-150-5p overexpression alone. Interestingly, a combination of mir-150-5p transfection with low doses GC in MM1S cells was found to sensitize therapy response, whereas opposite effects could be observed with a mir-150-5p specific antagomir. Although mir-150-5p overexpression did not substantially change GR expression levels, it was found that mir-150-5p evokes GR specific effects through indirect mRNA regulation of GR interacting transcription factors and hormone receptors, GR chaperones, as well as various effectors of unfolded protein stress and chemokine signalling. Altogether GC-inducible mir-150-5p adds another level of regulation to GC specific therapeutic responses in multiple myeloma.
Highlights
Multiple myeloma (MM) is a B-cell neoplasm characterized by the accumulation of clonal malignant plasma cells in the bone marrow and often correlated with various cytogenetic abnormalities such as del(13), t(11:14), non-hyperdiploidy, and del(17p) [1, 2]
MM1S and MM1R cells were left untreated or treated with 1 mM of the synthetic GC agonist dexamethasone (Dex) for respectively 6 h, 24 h, 48 h, 72 h. mRNA and proteins were isolated at each time point and analysed for corresponding NR3C1/GRa expression
We identified 30 GC inducible and 14 GC repressed microRNAs which might modulate multiple aspects of GC therapy response in MM, including cell cycle, cell proliferation, DNA replication, gene expression and cell death pathways
Summary
Multiple myeloma (MM) is a B-cell neoplasm characterized by the accumulation of clonal malignant plasma cells in the bone marrow and often correlated with various cytogenetic abnormalities such as del(13), t(11:14), non-hyperdiploidy, and del(17p) [1, 2]. Therapy against multiple myeloma consists of drugs which can decrease the clonal plasma cell population. Initial treatment towards the disease depends mainly on patients age and comorbidities. For patients under the age of 65 high doses of chemotherapy of different combinations such as thalidomide– dexamethasone-bortezomib based regimens, and lenalidomide–dexamethasone followed by autologous haematopoietic stem cell transplantation has been a practice in the clinic in the recent years [4, 5, 6, 7, 8]. Numerous novel drug combinations are currently being tested to prevent resistance and improve GC efficacy in the therapy of lymphoid malignancies [9]
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