Prostaglandin E1 Inhibits GLI2 Amplification-Associated Activation of the Hedgehog Pathway and Drug Refractory Tumor Growth
Prostaglandin E1 Inhibits GLI2 Amplification-Associated Activation of the Hedgehog Pathway and Drug Refractory Tumor Growth
复制标题
前列腺素 E1 抑制 GLI2 扩增相关的 Hedgehog 通路激活和药物难治性肿瘤生长
DOI：
10.1158/0008-5472.can-19-2052
复制
发表时间：
2020-07-01
期刊：
影响因子：
11.2
通讯作者：
Wang, Yu
中科院分区：
文献类型：
--
作者：
Wu, Fujia;Zhang, Chenze;Wang, Yu
Hedgehog(HH)信号通路的异常激活强调了多种癌症的发生和发展。主要药物vismodegib(GDC-0449)和sonidegib(LDE225)都是Smoothens(SMO)拮抗剂，由于获得了改变途径成分的突变，特别是SMO的次级突变和途径末端转录中介GLI2的扩增，其有效性受到影响。药物阻断GLI2活性可以最终克服这些多样化的难治性机制，这在比目前的SMO拮抗剂更广泛的原发肿瘤中也是有效的。为此，我们进行了高含量的筛选，直接分析了GLI2的纤毛转位，GLI2是HH信号转导中GLI2激活的关键事件。几种前列腺素化合物被证明能抑制GLI2在初级纤毛(PC)中的聚集。特别是，FDA批准的药物前列腺素E1(PGE1)是一种有效的GLI2拮抗剂，它克服了SMO突变和GLI2扩增的耐药机制。EP4受体定位于PC，与HH途径的调节作用一致。在机制上，PGE1通过EP4受体抑制HH信号，增强cAMP-PKA活性，进而通过泛素化途径促进GLI2的磷酸化和降解。PGE1还能有效抑制耐药人髓母细胞瘤的生长。总之，这些结果确定PGE1和其他前列腺素是潜在的补充治疗开发的模板，以规避临床上使用的当代SMO拮抗剂的耐药性。意义：这些发现表明，对于Hedgehog靶向治疗，PGE1对多种药物耐药活性表现出泛抑制作用，并在模仿GLI2扩增的药物难治性人髓母细胞瘤异种移植模型中产生显著的抗肿瘤作用。
Aberrant activation of the Hedgehog (HH) signaling pathway underlines the initiation and progression of a multitude of cancers. The effectiveness of the leading drugs vismodegib (GDC-0449) and sonidegib (LDE225), both Smoothened (SMO) antagonists, is compromised by acquisition of mutations that alter pathway components, notably secondary mutations in SMO and amplification of GLI2, a transcriptional mediator at the end of the pathway. Pharmacologic blockade of GLI2 activity could ultimately overcome these diversified refractory mechanisms, which would also be effective in a broader spectrum of primary tumors than current SMO antagonists. To this end, we conducted a high-content screening directly analyzing the ciliary translocation of GLI2, a key event for GLI2 activation in HH signal transduction. Several prostaglandin compounds were shown to inhibit accumulation of GLI2 within the primary cilium (PC). In particular, prostaglandin E1 (PGE1), an FDA-approved drug, is a potent GLI2 antagonist that overcame resistance mechanisms of both SMO mutagenesis and GLI2 amplification. Consistent with a role in HH pathway regulation, EP4 receptor localized to the PC. Mechanistically, PGE1 inhibited HH signaling through the EP4 receptor, enhancing cAMP-PKA activity, which promoted phosphorylation and degradation of GLI2 via the ubiquitination pathway. PGE1 also effectively inhibited the growth of drug refractory human medullo-blastoma xenografts. Together, these results identify PGE1 and other prostaglandins as potential templates for complementary therapeutic development to circumvent resistance to current generation SMO antagonists in use in the clinic.Significance: These findings show that PGE1 exhibits pan-inhibition against multiple drug refractory activities for Hedgehog-targeted therapies and elicits significant antitumor effects in xenograft models of drug refractory human medullo-blastoma mimicking GLI2 amplification.