A Novel Combination Approach Targeting an Enhanced Protein Synthesis Pathway in MYC-driven (Group 3) Medulloblastoma
A Novel Combination Approach Targeting an Enhanced Protein Synthesis Pathway in MYC-driven (Group 3) Medulloblastoma
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DOI：
10.1158/1535-7163.mct-19-0996
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发表时间：
2020-06-01
影响因子：
5.7
通讯作者：
Coulter, Don W.
中科院分区：
文献类型：
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作者：
Chaturvedi, Nagendra K.;Kling, Matthew J.;Coulter, Don W.
MYC癌基因在髓母细胞瘤患者中经常扩增，特别是在预后最差的第3组患者中。mTOR信号驱动的失调蛋白质合成在各种癌症中非常常见，包括髓母细胞瘤，可以促进MYC稳定。作为转录因子，MYC本身还已知调节蛋白质合成机制的几种组分的转录，导致蛋白质合成速率和增殖的增强。因此，通过共同靶向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高度相关策略。在这里，我们使用siRNA和小分子抑制剂方法，评估了MYC转录和mTOR信号传导的联合抑制对MYC扩增的（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/存活的影响以及相关的分子机制。联合抑制MYC和mTOR可协同抑制髓母细胞瘤细胞生长并诱导G（1）细胞周期阻滞和凋亡。在机制上，组合抑制显著下调MYC和mTOR信号传导的关键靶蛋白的表达水平。我们的RNA测序结果显示，联合抑制协同调节包括MYC/mTOR组分的全局基因表达。此外，与单药治疗相比，联合治疗通过下调MYC和mTOR信号传导的关键下游组分的表达，显著延迟了肿瘤生长并延长了MYC扩增的髓母细胞瘤异种移植小鼠的生存期。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驱动的髓母细胞瘤的新治疗方法。
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 G(1) 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 induding 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.