A study on restroration of glucocorticoid sensitivity by regulating SR protein

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Glucocorticoid (GC) resistance loses therapeutic options for patients with hematopoietic malignancies. Here we present the novel strategy to overcome GC resistance by modulating splicing regulation of GC receptors (GR) in acute lymphoblastic leukemia (ALL). Dexamethasone exhibited its effects on GC resistant ALL cells when it was administered with a NF-kappaB inhibitor. NF-kappaB inhibition reduced PU.1 and serine-arginine-rich (SR) protein p30c, leading to the increase in a functional isoform but not a dominant negative isoform of GR. PU.1 silencing upregulated total GR pre-mRNA expression, though SRp30c silencing elevated the functional GR. Blocking of the SRp30c binding site in GR pre-mRNA with complementary oligonucleotide restored GC resistance in vivo. We provide the first evidence that NF-kappaB activation induces GC resistance by promoting GR splicing with SRp30c, and blocking of SRp30c binding to GR pre-mRNA accelerates the GC sensitivity by inducing the functional GR.