Apigenin blocks IKKα activation and suppresses prostate cancer progression.
Apigenin blocks IKKα activation and suppresses prostate cancer progression.
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DOI：
10.18632/oncotarget.5157
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发表时间：
2015-10-13
期刊：
影响因子：
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通讯作者：
Gupta S
中科院分区：
文献类型：
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作者：
Shukla S;Kanwal R;Shankar E;Datt M;Chance MR;Fu P;MacLennan GT;Gupta S
IKKα被认为是肿瘤发生的关键调节因子和转移过程的驱动因子;因此被认为是抗癌药物开发中有前途的治疗靶点。尽管IKK抑制剂的开发取得了进展，但尚未发现强效IKKα抑制剂。我们的分子模拟和直接结合的多步骤方法已经鉴定出植物黄酮芹菜素是一种特异性IKKα抑制剂。本文报道了芹菜素在微摩尔浓度范围内抑制IKKα激酶活性，在功能细胞检测中显示抗增殖和抗侵袭活性，并在实验性肿瘤模型中显示抗癌功效。我们发现芹菜素直接与IKKα结合，减弱IKKα激酶活性，并抑制人前列腺癌PC-3和22 Rv 1细胞中NF-κ B/p65的活化，比IKK抑制剂PS1145更有效。我们还发现，芹菜素引起的细胞周期阻滞类似于前列腺癌细胞中IKKα的敲低。在异种移植小鼠模型中的研究表明，芹菜素喂养抑制肿瘤生长，降低增殖并增强凋亡。这些作用与抑制p-IKKα、NF-κ B/p65、增殖细胞核抗原和增加切割的caspase 3表达相关，呈剂量依赖性。总体而言，我们的结果表明，芹菜素抑制细胞增殖、侵袭力和肿瘤生长的减少是通过其抑制IKKα和影响NF-κ B信号通路的下游靶点的能力介导的。
IKKα has been implicated as a key regulator of oncogenesis and driver of the metastatic process; therefore is regarded as a promising therapeutic target in anticancer drug development. In spite of the progress made in the development of IKK inhibitors, no potent IKKα inhibitor(s) have been identified. Our multistep approach of molecular modeling and direct binding has led to the identification of plant flavone apigenin as a specific IKKα inhibitor. Here we report apigenin, in micro molar range, inhibits IKKα kinase activity, demonstrates anti-proliferative and anti-invasive activities in functional cell based assays and exhibits anticancer efficacy in experimental tumor model. We found that apigenin directly binds with IKKα, attenuates IKKα kinase activity and suppresses NF-ĸB/p65 activation in human prostate cancer PC-3 and 22Rv1 cells much more effectively than IKK inhibitor, PS1145. We also showed that apigenin caused cell cycle arrest similar to knockdown of IKKα in prostate cancer cells. Studies in xenograft mouse model indicate that apigenin feeding suppresses tumor growth, lowers proliferation and enhances apoptosis. These effects correlated with inhibition of p-IKKα, NF-ĸB/p65, proliferating cell nuclear antigen and increase in cleaved caspase 3 expression in a dose-dependent manner. Overall, our results suggest that inhibition of cell proliferation, invasiveness and decrease in tumor growth by apigenin are mediated by its ability to suppress IKKα and downstream targets affecting NF-ĸB signaling pathways.