Oblinger Janet L, Burns Sarah S, Huang Jie, Pan Li, Ren Yulin, Shen Rulong, Kinghorn A Douglas, Welling D Bradley, Chang Long-Sheng
Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, OH, USA.
Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, OH, USA.
Exp Neurol. 2018 Jan;299(Pt B):299-307. doi: 10.1016/j.expneurol.2017.06.015. Epub 2017 Jun 10.
Meningiomas frequently display activation of the PI3K/AKT/mTOR pathway, leading to elevated levels of phospho-eukaryotic translation initiation factor 4E binding proteins, which enhances protein synthesis; however, it is not known whether inhibition of protein translation is an effective treatment option for meningiomas. We found that human meningiomas expressed high levels of the three components of the eukaryotic initiation factor 4F (eIF4F) translation initiation complex, eIF4A, eIF4E, and eIF4G. The expression of eIF4A and eIF4E was important in sustaining the growth of NF2-deficient benign meningioma Ben-Men-1 cells, as shRNA-mediated knockdown of these proteins strongly reduced cell proliferation. Among a series of 23 natural compounds evaluated, silvestrol, which inhibits eIF4A, was identified as being the most growth inhibitory in both primary meningioma and Ben-Men-1 cells. Silvestrol treatment of meningioma cells prominently induced G/M arrest. Consistently, silvestrol significantly decreased the amounts of cyclins D1, E1, A, and B, PCNA, and Aurora A. In addition, total and phosphorylated AKT, ERK, and FAK, which have been shown to be important drivers for meningioma cell proliferation, were markedly lower in silvestrol-treated Ben-Men-1 cells. Our findings suggest that inhibiting protein translation could be a potential treatment for meningiomas.
脑膜瘤常常表现出PI3K/AKT/mTOR信号通路的激活，导致磷酸化的真核生物翻译起始因子4E结合蛋白水平升高，从而增强蛋白质合成；然而，抑制蛋白质翻译是否是治疗脑膜瘤的有效方法尚不清楚。我们发现，人类脑膜瘤表达高水平的真核生物翻译起始因子4F（eIF4F）翻译起始复合物的三个组分，即eIF4A、eIF4E和eIF4G。eIF4A和eIF4E的表达对于维持NF2缺陷型良性脑膜瘤Ben-Men-1细胞的生长很重要，因为shRNA介导的这些蛋白敲低显著降低了细胞增殖。在评估的一系列23种天然化合物中，抑制eIF4A的喜树碱被确定为对原发性脑膜瘤和Ben-Men-1细胞生长抑制作用最强的化合物。喜树碱处理脑膜瘤细胞显著诱导G/M期阻滞。同样，喜树碱显著降低了细胞周期蛋白D1、E1、A和B、增殖细胞核抗原（PCNA）以及极光激酶A的含量。此外，已被证明是脑膜瘤细胞增殖重要驱动因子的总AKT、磷酸化AKT、ERK和FAK，在喜树碱处理的Ben-Men-1细胞中明显较低。我们的研究结果表明，抑制蛋白质翻译可能是治疗脑膜瘤的一种潜在方法。
