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.