Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer
Minocycline Targets the NF-κB Nexus through Suppression of TGF-β1-TAK1-IκB Signaling in Ovarian Cancer
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DOI：
10.1158/1541-7786.mcr-13-0239
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发表时间：
2013-10-01
影响因子：
5.2
通讯作者：
Pourgholami, Mohammad H.
中科院分区：
文献类型：
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作者：
Ataie-Kachoie, Parvin;Badar, Samina;Pourgholami, Mohammad H.
大量证据支持NF-κ B B在卵巢癌中的关键作用。米诺环素，一种四环素，已被证明通过调节与NF-κ B转录组显著重叠的一组基因在这种恶性肿瘤中表现出有益作用。在此，使用体外和体内模型的组合来检查分子机制是否可归因于NF-κ B信号传导的调节。米诺环素抑制OVCAR-3和SKOV-3卵巢癌细胞中的组成性NF-κ B活化，并与I κ B α激酶（IKK）活化、I κ B α磷酸化和降解以及p65磷酸化和核转位的减弱相关。发现IKK的抑制与TGF-β激活的激酶-1（TAK 1）活化的抑制及其与TAK 1结合蛋白-1（TAB 1）的解离有关，TAB 1是TGF-β和TAK 1之间不可或缺的功能性介质。进一步的研究表明，米诺环素下调TGF-β 1的表达。TGF-β 1表达增强可诱导NF-κ B活性，米诺环素可挽救该效应。与这一发现一致，TGF-β 1敲低抑制NF-κ B活化，并消除米诺环素对该转录因子的抑制作用。这些结果表明米诺环素诱导的NF-κ B活性抑制部分通过抑制TGF-β 1介导。此外，米诺环素对NF-κ B途径活化的影响在携带腹膜内OVCAR-3肿瘤的雌性裸鼠中进行了检查。米诺环素的急性和慢性给药均导致p65磷酸化和核转位的抑制，并伴有NF-κ B活性和其靶基因产物的内源性蛋白水平的下调。这些数据揭示了米诺环素作为一种靶向促癌基因TGF-β-NF-κ B轴的药物在卵巢cancer.Implications的治疗潜力：这一临床前研究支持卵巢癌管理将受益于米诺环素的概念。
Substantial evidence supports the critical role of NF-kappa B in ovarian cancer. Minocycline, a tetracycline, has been shown to exhibit beneficial effects in this malignancy through regulation of a cohort of genes that overlap significantly with the NF-kappa B transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-kappa B signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-kappa B activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of I kappa B alpha kinase (IKK) activation, I kappa B alpha phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-beta-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-beta and TAK1. Further studies demonstrated that minocycline downregulated TGF-beta 1 expression. Enforced TGF-beta 1 expression induced NF-kappa B activity, and minocycline rescued this effect. Consistent with this finding, TGF-beta 1 knockdown suppressed NF-kappa B activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-kappa B activity is mediated, in part, through inhibition of TGF-beta 1. Furthermore, the influence of minocycline on NF-kappa B pathway activation was examined in female nude mice harboring intraperitoneal OVCAR-3 tumors. Both acute and chronic administration of minocycline led to suppression of p65 phosphorylation and nuclear translocation accompanied by downregulation of NF-kappa B activity and endogenous protein levels of its target gene products. These data reveal the therapeutic potential of minocycline as an agent targeting the pro-oncogenic TGF-beta-NF-kappa B axis in ovarian cancer.Implications: This preclinical study lends support to the notion that ovarian cancer management would benefit from administration of minocycline.