GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis.
GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis.
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DOI：
10.18632/oncotarget.2569
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发表时间：
2014-12-15
期刊：
影响因子：
--
通讯作者：
Athar M
中科院分区：
文献类型：
--
作者：
Srivastava RK;Kaylani SZ;Edrees N;Li C;Talwelkar SS;Xu J;Palle K;Pressey JG;Athar M
横纹肌肉瘤（RMS）通常起源于骨骼肌。目前，复发和转移性RMS患者没有成功的治疗方法。RMS的分子发病机制因癌症亚型而异。一些胚胎RMS亚型是由sonic hedgehog （Shh）信号通路驱动的，而不是其他亚型。然而，Shh通路抑制剂，特别是平滑抑制剂，在动物中不是很有效。在这里，我们发现Shh通路效应器GLI1和/或GLI2在大多数RMS细胞中过度表达，并且GANT-61，一种特异性的GLI1/2抑制剂抑制胚胎和肺泡RMS细胞来源的异种移植物肿瘤的增殖，从而阻断它们的生长。与对照组相比，接受GANT-61治疗的小鼠肿瘤生长抑制率约为50%。增殖抑制与细胞周期进程减慢有关，这是由细胞周期蛋白D1/2/3和E的表达减少和伴随的p21的诱导介导的。GANT-61不仅降低了这些RMS中GLI1/2的表达，而且显著降低了AKT/mTOR信号通路。当与替西莫司或长春新碱等用于RMS治疗的化疗药物联合使用时，甘特-61的治疗作用显着增强。最后，驱动上皮间充质转化（EMT）的蛋白表达降低是残留肿瘤的特征。
Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.
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