Radiation-triggered Tumor Necrosis Factor (TNF) α-NFκB Cross-signaling Favors Survival Advantage in Human Neuroblastoma Cells
Radiation-triggered Tumor Necrosis Factor (TNF) α-NFκB Cross-signaling Favors Survival Advantage in Human Neuroblastoma Cells
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DOI：
10.1074/jbc.m110.193755
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发表时间：
2011-06-17
影响因子：
4.8
通讯作者：
Aravindan, Natarajan
中科院分区：
文献类型：
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作者：
Veeraraghavan, Jamunarani;Natarajan, Mohan;Aravindan, Natarajan
放射治疗后存活癌细胞中诱导的放射抗性可能与克隆选择相关，导致治疗部位的肿瘤再生长。以前我们报道过I κ B α的翻译后修饰激活NF κ B B以响应电离辐射（IR），并在调节凋亡信号中起关键作用。在此，我们研究了人神经母细胞瘤IR后NF κ B B的协调。体外（SH-SY 5 Y、SK-N-MC和IMR-32）和体内（异种移植）研究均显示，IR持续诱导NF κ B B DNA结合活性和NF κ B依赖性TNF α反式激活和分泌。包括沉默NF κ B转录、阻断翻译后NF κ B核输入、突变TNF受体、NF κ B或TNF α的过表达和生理诱导的方法精确地证明了IR后NF κ B -> TNF α-> NF κ B正反馈循环的起始和发生，其导致并维持NF κ B活化。在TNF受体沉默的细胞中，AP-1和SP-1的无效抑制证实了选择性TNF依赖性NF κ B调节。此外，IR增加了Birc 1，Birc 2和Birc 5的反式激活和翻译，并诱导代谢活性和克隆扩增。进一步定义该途径以表明IR诱导的功能性p65转录（而不是NF κ B1、NF κ B2或c-Rel）对于这些存活分子的活化和相关的存活优势是必需的。总之，这些结果首次证明了NF κ B B在IR反应中的功能协调，并进一步暗示p65依赖的生存优势和克隆扩增的启动可能与人神经母细胞瘤的不良预后相关。
Induced radioresistance in the surviving cancer cells after radiotherapy could be associated with clonal selection leading to tumor regrowth at the treatment site. Previously we reported that post-translational modification of I kappa B alpha activates NF kappa B in response to ionizing radiation (IR) and plays a key role in regulating apoptotic signaling. Herein, we investigated the orchestration of NF kappa B after IR in human neuroblastoma. Both in vitro (SH-SY5Y, SK-N-MC, and IMR-32) and in vivo (xenograft) studies showed that IR persistently induced NF kappa B DNA binding activity and NF kappa B-dependent TNF alpha transactivation and secretion. Approaches including silencing NF kappa B transcription, blocking post-translational NF kappa B nuclear import, muting TNF receptor, overexpression, and physiological induction of either NF kappa B or TNF alpha precisely demonstrated the initiation and occurrence of NF kappa B -> TNF alpha -> NF kappa B positive feedback cycle after IR that leads to and sustains NF kappa B activation. Selective TNF-dependent NF kappa B regulation was confirmed with futile inhibition of AP-1 and SP-1 in TNF receptor muted cells. Moreover, IR increased both transactivation and translation of Birc1, Birc2, and Birc5 and induced metabolic activity and clonal expansion. This pathway was further defined to show that IR-induced functional p65 transcription (not NF kappa B1, NF kappa B2, or c-Rel) is necessary for activation of these survival molecules and associated survival advantage. Together, these results demonstrate for the first time the functional orchestration of NF kappa B in response to IR and further imply that p65-dependent survival advantage and initiation of clonal expansion may correlate with an unfavorable prognosis of human neuroblastoma.