Katsori Anna-Maria, Palagani Ajay, Bougarne Nadia, Hadjipavlou-Litina Dimitra, Haegeman Guy, Vanden Berghe Wim
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
Laboratory of Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, Wilrijk 2610, Belgium.
Molecules. 2015 Jan 8;20(1):863-78. doi: 10.3390/molecules20010863.
In this study a series of curcumin analogues were evaluated for their ability to inhibit the activation of NF-κΒ, a transcription factor at the crossroads of cancer-inflammation. Our novel curcumin analogue BAT3 was identified to be the most potent NF-κB inhibitor and EMSA assays clearly showed inhibition of NF-κB/DNA-binding in the presence of BAT3, in agreement with reporter gene results. Immunofluorescence experiments demonstrated that BAT3 did not seem to prevent nuclear p65 translocation, so our novel analogue may interfere with NF-κB/DNA-binding or transactivation, independently of IKK2 regulation and NF-κB-translocation. Gene expression studies on endogenous NF-κB target genes revealed that BAT3 significantly inhibited TNF-dependent transcription of IL6, MCP1 and A20 genes, whereas an NF-κB independent target gene heme oxygenase-1 remained unaffected. In conclusion, we demonstrate that BAT3 seems to inhibit different cancer-related inflammatory targets in the NF-κB signaling pathway through a different mechanism in comparison to similar analogues, previously reported.
在本研究中，对一系列姜黄素类似物抑制NF-κB激活的能力进行了评估，NF-κB是癌症炎症交叉点处的一种转录因子。我们发现新型姜黄素类似物BAT3是最有效的NF-κB抑制剂，电泳迁移率变动分析（EMSA）实验清楚地表明，在存在BAT3的情况下，NF-κB与DNA的结合受到抑制，这与报告基因的结果一致。免疫荧光实验表明，BAT3似乎不会阻止核p65的易位，因此我们的新型类似物可能独立于IKK2调节和NF-κB易位，干扰NF-κB与DNA的结合或反式激活。对内源性NF-κB靶基因的基因表达研究表明，BAT3显著抑制IL6、MCP1和A20基因的TNF依赖性转录，而NF-κB非依赖性靶基因血红素加氧酶-1则不受影响。总之，我们证明，与先前报道的类似类似物相比，BAT3似乎通过不同的机制抑制NF-κB信号通路中不同的癌症相关炎症靶点。
