N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics.
N-Myc overexpression increases cisplatin resistance in neuroblastoma via deregulation of mitochondrial dynamics.
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DOI：
10.1038/cddiscovery.2016.82
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发表时间：
2016
影响因子：
7
通讯作者：
中科院分区：
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N-Myc是一种全局转录因子，其调节参与许多基本细胞过程的基因的表达，包括：核糖体生物发生、细胞周期和凋亡。一旦失调，N-Myc可以驱动许多这些基因的病理表达，这最终决定了其致癌潜力。N-Myc的过表达已被证明有助于肿瘤发生，最值得注意的是儿科肿瘤，神经母细胞瘤。在此，我们提供的证据表明，解除管制的N-Myc改变参与线粒体动力学的蛋白质的表达。我们发现，N-Myc过表达导致增加的线粒体网状融合继发于蛋白质表达的变化，由于异常的转录和翻译后调节。我们认为，在神经母细胞瘤中，响应于N-Myc扩增的线粒体网络的结构变化有助于肿瘤发展和维持的两个重要方面-生物能量改变和凋亡抗性。具体来说，我们发现N-Myc过表达细胞对暴露于低剂量顺铂的程序性细胞死亡具有抗性，并证明这依赖于线粒体融合的增加。我们推测这些线粒体结构和功能的改变可能对N-Myc扩增的神经母细胞瘤的侵袭性临床表型有重要作用。
N-Myc is a global transcription factor that regulates the expression of genes involved in a number of essential cellular processes including: ribosome biogenesis, cell cycle and apoptosis. Upon deregulation, N-Myc can drive pathologic expression of many of these genes, which ultimately defines its oncogenic potential. Overexpression of N-Myc has been demonstrated to contribute to tumorigenesis, most notably for the pediatric tumor, neuroblastoma. Herein, we provide evidence that deregulated N-Myc alters the expression of proteins involved in mitochondrial dynamics. We found that N-Myc overexpression leads to increased fusion of the mitochondrial reticulum secondary to changes in protein expression due to aberrant transcriptional and post-translational regulation. We believe the structural changes in the mitochondrial network in response to N-Myc amplification in neuroblastoma contributes to two important aspects of tumor development and maintenance—bioenergetic alterations and apoptotic resistance. Specifically, we found that N-Myc overexpressing cells are resistant to programmed cell death in response to exposure to low doses of cisplatin, and demonstrated that this was dependent on increased mitochondrial fusion. We speculate that these changes in mitochondrial structure and function may contribute significantly to the aggressive clinical ph9enotype of N-Myc amplified neuroblastoma.