A study on restroration of glucocorticoid sensitivity by regulating SR protein

糖皮质激素（GC）抵抗使造血系统恶性肿瘤患者失去治疗选择。在这里，我们提出了一种新的策略，以克服GC耐药，通过调节剪接调控GC受体（GR）在急性淋巴细胞白血病（ALL）。当地塞米松与NF-κ B抑制剂一起给药时，地塞米松对GC耐药ALL细胞表现出其作用。NF-κ B抑制减少PU.1和富含丝氨酸-精氨酸（SR）的蛋白p30 c，导致增加的功能亚型，但不是一个显性负性的GR亚型。PU.1沉默上调总GR前mRNA的表达，虽然SRp 30 c沉默提高功能GR。SRp 30 c结合位点的GR前mRNA与互补寡核苷酸阻断恢复GC抗性在体内。我们提供了第一个证据表明NF-κ B激活通过促进GR与SRp 30 c的剪接诱导GC抗性，并且阻断SRp 30 c与GR前mRNA的结合通过诱导功能性GR加速GC敏感性。

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.