3-Formylchromone Interacts with Cysteine 38 in p65 Protein and with Cysteine 179 in IκBα Kinase, Leading to Down-regulation of Nuclear Factor-κB (NF-κB)-regulated Gene Products and Sensitization of Tumor Cells (Retracted article. See vol. 291, pg. 16926, 2016)
3-Formylchromone Interacts with Cysteine 38 in p65 Protein and with Cysteine 179 in IκBα Kinase, Leading to Down-regulation of Nuclear Factor-κB (NF-κB)-regulated Gene Products and Sensitization of Tumor Cells (Retracted article. See vol. 291, pg. 16926, 2016)
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DOI：
10.1074/jbc.m111.274613
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发表时间：
2012-01-02
影响因子：
4.8
通讯作者：
Aggarwal, Bharat B.
中科院分区：
文献类型：
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作者：
Yadav, Vivek R.;Prasad, Sahdeo;Aggarwal, Bharat B.
3-甲酰色酮（3-FC）通过一种尚未阐明的机制与抗癌潜力相关。由于NF-κ B在肿瘤发生中的关键作用，我们研究了该试剂对NF-κ B活化途径的影响。无论是由炎症因子（如TNF-α和内毒素）或肿瘤促进剂（如佛波酯和冈田酸）激活，3-FC都抑制NF-κ B激活。它还抑制大多数肿瘤细胞表达的组成型NF-κ B。该活性与I κ B α激酶（IKK）激活、I κ B α磷酸化、I κ B α降解、p65磷酸化、p65核转位和报告基因表达的顺序抑制相关。我们发现，3-FC抑制p65与DNA的直接结合，这种结合被还原剂逆转，从而表明半胱氨酸残基的作用。此外，p65中Cys（38）突变为Ser消除了色酮的这种作用。这一结果得到了对接研究的证实。3-FC也直接抑制IKK激活，还原剂逆转了这种抑制作用。此外，IKK中Cys（179）突变为Ala消除了色酮的作用。抑制NF-κ B活化导致抗凋亡（Bcl-2、Bcl-x（L）、生存素和cIAP-1）、增殖（cyclinD（1）和考克斯-2）、侵袭（MMP-9和ICAM-1）和血管生成（VEGF）基因产物的抑制以及肿瘤细胞对细胞因子的敏感性。因此，本研究表明，3-FC修饰IKK和p65中的半胱氨酸残基可抑制NF-κ B活化途径，抑制抗凋亡基因产物，并增强肿瘤细胞的凋亡。
3-Formylchromone (3-FC) has been associated with anticancer potential through a mechanism yet to be elucidated. Because of the critical role of NF-kappa B in tumorigenesis, we investigated the effect of this agent on the NF-kappa B activation pathway. Whether activated by inflammatory agents (such as TNF-alpha and endotoxin) or tumor promoters (such as phorbol ester and okadaic acid), 3-FC suppressed NF-kappa B activation. It also inhibited constitutive NF-kappa B expressed by most tumor cells. This activity correlated with sequential inhibition of I kappa B alpha kinase (IKK) activation, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation, p65 nuclear translocation, and reporter gene expression. We found that 3-FC inhibited the direct binding of p65 to DNA, and this binding was reversed by a reducing agent, thus suggesting a role for the cysteine residue. Furthermore, mutation of Cys(38) to Ser in p65 abolished this effect of the chromone. This result was confirmed by a docking study. 3-FC also inhibited IKK activation directly, and the reducing agent reversed this inhibition. Furthermore, mutation of Cys(179) to Ala in IKK abolished the effect of the chromone. Suppression of NF-kappa B activation led to inhibition of anti-apoptotic (Bcl-2, Bcl-x(L), survivin, and cIAP-1), proliferative (cyclinD(1) and COX-2), invasive (MMP-9 and ICAM-1), and angiogenic (VEGF) gene products and sensitization of tumor cells to cytokines. Thus, this study shows that modification of cysteine residues in IKK and p65 by 3-FC leads to inhibition of the NF-kappa B activation pathway, suppression of anti-apoptotic gene products, and potentiation of apoptosis in tumor cells.