Professor and Head of Department of Surgery, Level 3 Pitney Building, St. George Hospital, Gray St., Kogarah, Sydney, NSW 2217, Australia.
Mol Cancer Res. 2013 Oct;11(10):1279-91. doi: 10.1158/1541-7786.MCR-13-0239. Epub 2013 Jul 15.
Substantial evidence supports the critical role of NF-κB 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-κB transcriptome. Here, it was examined whether or not the molecular mechanism could be attributed to modulation of NF-κB signaling using a combination of in vitro and in vivo models. Minocycline suppressed constitutive NF-κB activation in OVCAR-3 and SKOV-3 ovarian carcinoma cells and was correlated with attenuation of IκBα kinase (IKK) activation, IκBα phosphorylation and degradation, and p65 phosphorylation and nuclear translocation. The inhibition of IKK was found to be associated with suppression of TGF-β-activated-kinase-1 (TAK1) activation and its dissociation from TAK1-binding-protein-1 (TAB1), an indispensable functional mediator between TGF-β and TAK1. Further studies demonstrated that minocycline downregulated TGF-β1 expression. Enforced TGF-β1 expression induced NF-κB activity, and minocycline rescued this effect. Consistent with this finding, TGF-β1 knockdown suppressed NF-κB activation and abrogated the inhibitory effect of minocycline on this transcription factor. These results suggest that the minocycline-induced suppression of NF-κB activity is mediated, in part, through inhibition of TGF-β1. Furthermore, the influence of minocycline on NF-κB 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-κB 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-β-NF-κB axis in ovarian cancer.
This preclinical study lends support to the notion that ovarian cancer management would benefit from administration of minocycline.
大量证据支持 NF-κB 在卵巢癌中的关键作用。米诺环素是一种四环素，已被证明通过调节与 NF-κB 转录组显著重叠的一组基因，对这种恶性肿瘤具有有益的作用。在这里，使用体外和体内模型组合，检查分子机制是否归因于 NF-κB 信号的调节。米诺环素抑制 OVCAR-3 和 SKOV-3 卵巢癌细胞中组成性 NF-κB 激活，并与 IκBα 激酶 (IKK) 激活、IκBα 磷酸化和降解以及 p65 磷酸化和核易位的衰减相关。发现 IKK 的抑制与 TGF-β 激活激酶-1 (TAK1) 激活及其与 TAK1 结合蛋白-1 (TAB1) 的分离有关，后者是 TGF-β 和 TAK1 之间必不可少的功能介质。进一步的研究表明，米诺环素下调 TGF-β1 的表达。强制表达 TGF-β1 诱导 NF-κB 活性，米诺环素挽救了这种作用。与这一发现一致的是，TGF-β1 敲低抑制 NF-κB 激活，并取消了米诺环素对这种转录因子的抑制作用。这些结果表明，米诺环素诱导的 NF-κB 活性抑制部分是通过抑制 TGF-β1 介导的。此外，在携带腹腔内 OVCAR-3 肿瘤的雌性裸鼠中检查了米诺环素对 NF-κB 途径激活的影响。米诺环素的急性和慢性给药均导致 p65 磷酸化和核易位的抑制，同时 NF-κB 活性和其靶基因产物的内源性蛋白水平下调。这些数据揭示了米诺环素作为一种靶向卵巢癌中致癌性 TGF-β-NF-κB 轴的药物的治疗潜力。
这项临床前研究支持这样一种观点，即卵巢癌的管理将受益于米诺环素的给药。
