The MYC oncogene is frequently amplified in patients with medulloblastoma, particularly in group 3 patients, who have the worst prognosis. mTOR signaling–driven deregulated protein synthesis is very common in various cancers, including medulloblastoma, that can promote MYC stabilization. As a transcription factor, MYC itself is further known to regulate transcription of several components of protein synthesis machinery, leading to an enhanced protein synthesis rate and proliferation. Thus, inhibiting enhanced protein synthesis by targeting the MYC and mTOR pathways together may represent a highly relevant strategy for the treatment of MYC-driven medulloblastoma. Here, using siRNA and small-molecule inhibitor approaches, we evaluated the effects of combined inhibition of MYC transcription and mTOR signaling on medulloblastoma cell growth/survival and associated molecular mechanism(s) in MYC-amplified (group 3) medulloblastoma cell lines and xenografts. Combined inhibition of MYC and mTOR synergistically suppressed medulloblastoma cell growth and induced G1 cell-cycle arrest and apoptosis. Mechanistically, the combined inhibition significantly downregulated the expression levels of key target proteins of MYC and mTOR signaling. Our results with RNA-sequencing revealed that combined inhibition synergistically modulated global gene expression including MYC/mTOR components. In addition, the combination treatment significantly delayed tumor growth and prolonged survival of MYC-amplified medulloblastoma xenografted mice by downregulating expression of MYC and the key downstream components of mTOR signaling, compared with single-agent therapy. Together, our findings demonstrated that dual inhibition of MYC (transcription) and mTOR (translation) of the protein synthesis pathway can be a novel therapeutic approach against MYC-driven medulloblastoma.

中文翻译：

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一种针对 MYC 驱动（第 3 组）成神经管细胞瘤中增强的蛋白质合成途径的新型组合方法

MYC 癌基因在髓母细胞瘤患者中经常扩增，尤其是在预后最差的第 3 组患者中。mTOR 信号驱动的蛋白质合成失调在包括髓母细胞瘤在内的各种癌症中非常常见，可以促进 MYC 稳定。作为一种转录因子，MYC 本身还可以调节蛋白质合成机制的几种成分的转录，从而提高蛋白质合成速率和增殖。因此，通过同时靶向 MYC 和 mTOR 通路来抑制增强的蛋白质合成可能代表了治疗 MYC 驱动的髓母细胞瘤的一种高度相关的策略。在这里，使用 siRNA 和小分子抑制剂方法，我们评估了 MYC 转录和 mTOR 信号传导的联合抑制对 MYC 扩增（第 3 组）成神经管细胞瘤细胞系和异种移植物中成神经管细胞瘤细胞生长/存活和相关分子机制的影响。MYC 和 mTOR 的联合抑制协同抑制成神经管细胞瘤细胞生长并诱导 G1 细胞周期停滞和细胞凋亡。从机制上讲，联合抑制显着下调 MYC 和 mTOR 信号传导的关键靶蛋白的表达水平。我们的 RNA 测序结果表明，联合抑制协同调节全局基因表达，包括 MYC/mTOR 成分。此外，与单药治疗相比，联合治疗通过下调 MYC 的表达和 mTOR 信号传导的关键下游成分，显着延迟了 MYC 扩增的成神经管细胞瘤异种移植小鼠的肿瘤生长并延长了存活期。总之，我们的研究结果表明，蛋白质合成途径的 MYC（转录）和 mTOR（翻译）的双重抑制可能是一种针对 MYC 驱动的成神经管细胞瘤的新型治疗方法。