Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
PLoS One. 2013 Aug 14;8(8):e72464. doi: 10.1371/journal.pone.0072464. eCollection 2013.
Recently, we demonstrated that radiation (IR) instigates the occurrence of a NFκB-TNFα feedback cycle which sustains persistent NFκB activation in neuroblastoma (NB) cells and favors survival advantage and clonal expansion. Further, we reported that curcumin targets IR-induced survival signaling and NFκB dependent hTERT mediated clonal expansion in human NB cells. Herein, we investigated the efficacy of a novel synthetic monoketone, EF24, a curcumin analog in inhibiting persistent NFκB activation by disrupting the IR-induced NFκB-TNFα-NFκB feedback signaling in NB and subsequent mitigation of survival advantage and clonal expansion. EF24 profoundly suppressed the IR-induced NFκB-DNA binding activity/promoter activation and, maintained the NFκB repression by deterring NFκB-dependent TNFα transactivation/intercellular secretion in genetically varied human NB (SH-SY5Y, IMR-32, SK-PN-DW, MC-IXC and SK-N-MC) cell types. Further, EF24 completely suppressed IR-induced NFκB-TNFα cross-signaling dependent transactivation/translation of pro-survival IAP1, IAP2 and Survivin and subsequent cell survival. In corroboration, EF24 treatment maximally blocked IR-induced NFκB dependent hTERT transactivation/promoter activation, telomerase activation and consequent clonal expansion. EF24 displayed significant regulation of IR-induced feedback dependent NFκB and NFκB mediated survival signaling and complete regression of NB xenograft. Together, the results demonstrate for the first time that, novel synthetic monoketone EF24 potentiates radiotherapy and mitigates NB progression by selectively targeting IR-triggered NFκB-dependent TNFα-NFκB cross-signaling maintained NFκB mediated survival advantage and clonal expansion.
最近，我们证明了辐射（IR）引发了 NFκB-TNFα 反馈循环的发生，该循环维持了神经母细胞瘤（NB）细胞中持续的 NFκB 激活，并有利于生存优势和克隆扩增。此外，我们报道姜黄素靶向 IR 诱导的生存信号和 NFκB 依赖性 hTERT 介导的人类 NB 细胞的克隆扩增。在此，我们研究了新型合成单酮 EF24 的功效，姜黄素类似物通过破坏 IR 诱导的 NFκB-TNFα-NFκB 反馈信号来抑制持续的 NFκB 激活，从而抑制 NB 中的 NFκB 依赖性 hTERT 介导的克隆扩增，并随后减轻生存优势和克隆扩增。EF24 可显著抑制 IR 诱导的 NFκB-DNA 结合活性/启动子激活，并通过阻止 NFκB 依赖性 TNFα 转激活/细胞间分泌来维持 NFκB 抑制，从而在遗传多样化的人类 NB（SH-SY5Y、IMR-32、SK-PN-DW、MC-IXC 和 SK-N-MC）细胞类型中抑制 NFκB 依赖性 TNFα 转激活/细胞间分泌。此外，EF24 完全抑制了 IR 诱导的 NFκB-TNFα 交叉信号依赖性的促生存 IAP1、IAP2 和 Survivin 的转激活/翻译，以及随后的细胞存活。此外，EF24 治疗最大程度地阻断了 IR 诱导的 NFκB 依赖性 hTERT 转激活/启动子激活、端粒酶激活和随后的克隆扩增。EF24 对 IR 诱导的反馈依赖的 NFκB 和 NFκB 介导的生存信号具有显著的调节作用，并完全消退了 NB 异种移植。总之，这些结果首次证明，新型合成单酮 EF24 通过选择性靶向 IR 触发的 NFκB 依赖性 TNFα-NFκB 交叉信号，增强放射治疗并减轻 NB 进展，从而维持 NFκB 介导的生存优势和克隆扩增。
