Abstract：
Tumor MYCN amplification is seen in high-risk neuroblastoma, yet direct targeting of this oncogenic transcription factor has been challenging. Here, we take advantage of the dependence of MYCN-amplified neuroblastoma cells on increased protein synthesis to inhibit the activity of eukaryotic translation initiation factor 4A1 (eIF4A1) using an amidino-rocaglate, CMLD012824. Consistent with the role of this RNA helicase in resolving structural barriers in 5\' untranslated regions (UTRs), CMLD012824 increased eIF4A1 affinity for polypurine-rich 5\' UTRs, including that of the MYCN and associated transcripts with critical roles in cell proliferation. CMLD012824-mediated clamping of eIF4A1 spanned the full lengths of mRNAs, while translational inhibition was mediated through 5\' UTR binding in a cap-dependent and -independent manner. Finally, CMLD012824 led to growth inhibition in MYCN-amplified neuroblastoma models without generalized toxicity. Our studies highlight the key role of eIF4A1 in MYCN-amplified neuroblastoma and demonstrate the therapeutic potential of disrupting its function.
摘要：
肿瘤MYCN扩增见于高危神经母细胞瘤,然而,这种致癌转录因子的直接靶向一直具有挑战性.这里,我们利用MYCN扩增的神经母细胞瘤细胞对增加的蛋白质合成的依赖性来抑制真核翻译起始因子4A1（eIF4A1）的活性，CMLD012824。与该RNA解旋酶在解决5'非翻译区（UTR）的结构障碍中的作用一致，CMLD012824增加了eIF4A1对富含多嘌呤的5'UTR的亲和力，包括MYCN和在细胞增殖中起关键作用的相关转录本。CMLD012824介导的eIF4A1钳制跨越了mRNA的全长，而翻译抑制是通过5'UTR结合以帽依赖性和非依赖性方式介导的。最后,CMLD012824在MYCN扩增的神经母细胞瘤模型中导致生长抑制，而没有全身毒性。我们的研究强调了eIF4A1在MYCN扩增的神经母细胞瘤中的关键作用，并证明了破坏其功能的治疗潜力。
