Novel synthetic monoketone transmute radiation-triggered NFκB-dependent TNFα cross-signaling feedback maintained NFκB and favors neuroblastoma regression.
Novel synthetic monoketone transmute radiation-triggered NFκB-dependent TNFα cross-signaling feedback maintained NFκB and favors neuroblastoma regression.
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DOI：
10.1371/journal.pone.0072464
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Aravindan N
中科院分区：
文献类型：
--
作者：
Aravindan S;Natarajan M;Awasthi V;Herman TS;Aravindan N
最近，我们发现辐射（IR）可诱导NFκB-TNFα反馈循环的发生，该循环可维持神经母细胞瘤（NB）细胞中NFκB的持续活化，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NB细胞克隆扩增。在此，我们研究了一种新的合成单酮，EF 24，姜黄素类似物，通过破坏NB中IR诱导的NFκB-TNFα-NFκB反馈信号抑制NFκB B持续活化的功效，以及随后的生存优势和克隆扩增的缓解。EF 24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NFκ B依赖性TNFα的反式激活/细胞间分泌维持NFκB B抑制。此外，EF 24完全抑制IR诱导的NFκB-TNFα交叉信号依赖性促存活IAP 1、IAP 2和Survivin的反式激活/翻译以及随后的细胞存活。进一步证实，EF 24处理最大程度地阻断了IR诱导的NFκB依赖性hTERT反式激活/启动子激活、端粒酶激活和随后的克隆扩增。EF 24对IR诱导的反馈依赖性NFκB和NFκB介导的存活信号传导具有显著调节作用，并使NB异种移植物完全消退。总之，这些结果首次证明，新型合成单酮EF 24通过选择性靶向IR触发的NFκ B依赖性TNFα-NFκB交叉信号传导维持NFκB B介导的存活优势和克隆扩增，增强放射治疗并减轻NB进展。
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.
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影响因子：
2.3
作者：
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通讯作者：
Shoji, M
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影响因子：
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作者：
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通讯作者：
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