Targeting of glioma stem-like cells with a parthenolide derivative ACT001 through inhibition of AEBP1/PI3K/AKT signaling.
Targeting of glioma stem-like cells with a parthenolide derivative ACT001 through inhibition of AEBP1/PI3K/AKT signaling.
复制标题
小白菊内酯衍生物 ACT001 通过抑制 AEBP1/PI3K/AKT 信号传导靶向神经胶质瘤干样细胞
作者：
Hou Y;Sun B;Liu W;Yu B;Shi Q;Luo F;Bai Y;Feng H
胶质母细胞瘤（GBM）是成人中最致命的原发性脑肿瘤，中位生存期约为15个月。一种潜在的治疗策略涉及靶向胶质瘤干细胞样细胞（GSC），这些细胞能够启动、维持和重新填充肿瘤块。在这里，我们确定ACT 001，一种孤雌菊衍生物，通过调节脂肪细胞增强子结合蛋白1（AEBP 1）信号传导靶向GSC。方法：观察ACT 001对正常人星形胶质细胞（NHA）和胶质瘤干细胞（GSC）存活的影响。通过RNA-Seq检测差异表达基因。使用GSC原位异种移植模型评估ACT 001作为单药或与SHP-2抑制剂SHP 099组合的功效。结果：与正常人星形胶质细胞相比，GSC对ACT 001表现出高反应性。通过RNA-Seq分析，AEBP 1是ACT 001的推定靶点，其表达与GBM患者的预后相关。AEBP 1的敲低抑制GSC增殖和胶质瘤球形成。用ACT 001或PI 3 K抑制剂或AEBP 1消耗处理将损害AKT磷酸化和GSC增殖，而组成性AKT活化拯救ACT 001处理或AEBP 1消耗抑制的细胞增殖。此外，ACT 001阻断GSC中TGF-β激活的AEBP 1/AKT信号传导。ACT 001单药或与SHP 099联合给药均显示出抗肿瘤活性，这为携带GSC肿瘤异种移植物的动物提供了显著的生存获益。结论：我们的数据表明，AEBP 1是GBM的一个新的可药用靶点，ACT 001是一种潜在的治疗选择，可与SHP 099联合改善GBM的临床治疗。
Glioblastoma (GBM) is the most lethal primary brain tumor in adults with a median survival of around 15 months. A potential treatment strategy involves targeting glioma stem-like cells (GSCs) that are able to initiate, maintain, and repopulate the tumor mass. Here, we identify ACT001, a parthenolide derivative, targeting GSCs through regulation of adipocyte enhancer binding protein 1 (AEBP1) signaling. Methods: The effects of ACT001 on cell survival of normal human astrocytes (NHA) and patient-derived glioma stem-like cells (GSCs) were evaluated. RNA-Seq were performed to detect differentially expressed genes. ACT001 efficacy as a single agent or in combination with SHP-2 inhibitor SHP099 was assessed using a GSC orthotopic xenograft model. Results: GSCs exhibit high response to ACT001 in compared with normal human astrocytes. AEBP1 is a putative target of ACT001 by RNA-Seq analysis, which expression associates with prognosis of GBM patients. Knockdown of AEBP1 inhibits GSC proliferation and glioma sphere formation. Treatment with ACT001 or PI3K inhibitor or AEBP1 depletion would impair AKT phosphorylation and GSC proliferation, whereas constitutive AKT activation rescues ACT001 treatment or AEBP1 depletion-inhibited cell proliferation. Moreover, ACT001 blocks TGF-β-activated AEBP1/AKT signaling in GSCs. ACT001 exhibits antitumor activity either as a single agent or in combination with SHP099, which provides significant survival benefits for GSC tumor xenograft-bearing animals. Conclusions: Our data demonstrate AEBP1 as a new druggable target in GBM and ACT001 as a potential therapeutic option for improving the clinical treatment of GBM in combination with SHP099.