MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma.
MYCN expression induces replication stress and sensitivity to PARP inhibition in neuroblastoma.
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DOI：
10.18632/oncotarget.27329
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发表时间：
2020-06-09
期刊：
影响因子：
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通讯作者：
Bryant, Helen E
中科院分区：
文献类型：
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作者：
King, David;Li, Xiao Dun;Bryant, Helen E
本研究探讨了MYCN癌基因表达对神经母细胞瘤DNA损伤反应、复制叉进展和对PARP抑制的敏感性的影响。在一组神经母细胞瘤细胞系中，与非表达/扩增细胞中观察到的反应相比，MYCN扩增或MYCN表达导致对一系列PARP抑制剂（Niraparib、Veliparib、talazoparib和olaparib）的反应增加。MYCN表达减慢了复制叉的速度，增加了复制叉的停滞，这种作用通过PARP抑制或PARP 1耗尽而放大。在S期细胞中特异性地诱导所见的DNA损伤增加。重要的是，在表达MYCN的神经母细胞瘤转基因鼠模型中，PARP抑制导致携带表达MYCN的肿瘤的小鼠的存活率显著增加。奥拉帕尼还使MYCN表达细胞对喜树碱和替莫唑胺诱导的细胞死亡的敏感程度高于非表达细胞。总之，MYCN表达导致神经母细胞瘤细胞中复制应激增加。这种作用被PARP的抑制所放大，导致S期特异性DNA损伤并最终增加肿瘤细胞死亡。因此，PARP抑制单独或与经典化疗药物组合是神经母细胞瘤的潜在治疗策略，并且在MYCN表达肿瘤中可能更有效。
This study investigates the influence expression of the MYCN oncogene has on the DNA damage response, replication fork progression and sensitivity to PARP inhibition in neuroblastoma. In a panel of neuroblastoma cell lines, MYCN amplification or MYCN expression resulted in increased cell death in response to a range of PARP inhibitors (niraparib, veliparib, talazoparib and olaparib) compared to the response seen in non-expressing/amplified cells. MYCN expression slowed replication fork speed and increased replication fork stalling, an effect that was amplified by PARP inhibition or PARP1 depletion. Increased DNA damage seen was specifically induced in S-phase cells. Importantly, PARP inhibition caused a significant increase in the survival of mice bearing MYCN expressing tumours in a transgenic murine model of MYCN expressing neuroblastoma. Olaparib also sensitized MYCN expressing cells to camptothecin- and temozolomide-induced cell death to a greater degree than non-expressing cells. In summary, MYCN expression leads to increased replication stress in neuroblastoma cells. This effect is exaggerated by inhibition of PARP, resulting in S-phase specific DNA damage and ultimately increased tumour cell death. PARP inhibition alone or in combination with classical chemotherapeutics is therefore a potential therapeutic strategy for neuroblastoma and may be more effective in MYCN expressing tumours.