Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer
Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer
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基于系统生物学网络发现靶向 AMPK/ZIPK 并诱导宫颈癌细胞凋亡的小分子激活剂 BL-AD008
DOI：
10.18632/oncotarget.3513
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发表时间：
2015-04-10
期刊：
影响因子：
--
通讯作者：
Huang, Jian
中科院分区：
文献类型：
--
作者：
Fu, Leilei;Zhang, Shouyue;Huang, Jian
本研究旨在寻找一种靶向AMPK/ZIPK并诱导宫颈癌细胞凋亡的小分子激活剂BL-AD 008。在这项研究中，我们系统地构建了全球蛋白质-蛋白质相互作用（PPI）网络，并通过朴素贝叶斯模型预测了糖尿病相关的蛋白质连接。然后，我们确定了一些经典的凋亡PPI和其他以前未被认识的PPI之间的凋亡激酶，如AMPK和ZIPK。随后，我们筛选了一系列以AMPK/ZIPK为靶点的候选化合物，并合成了部分化合物，最终发现了一种新型的双靶点激活剂（BL-AD 008）。此外，我们发现BL-AD 008对宫颈癌细胞具有显著的抗增殖活性，并可通过死亡受体和线粒体途径诱导细胞凋亡。此外，我们发现BL-AD 008诱导的凋亡受到AMPK和ZIPK组合的影响。结果表明，BL-AD 008具有抗肿瘤活性，并能通过AMPK/ZIPK靶向作用诱导肿瘤细胞凋亡。总之，这些结果证明了系统生物学网络识别一些关键凋亡激酶靶点AMPK和ZIPK的能力;从而提供了双靶点小分子激活剂（BL-AD 008）作为未来宫颈癌治疗中潜在的新的凋亡调节药物。
The aim of this study was to discover a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. In this study, we systematically constructed the global protein-protein interaction (PPI) network and predicted apoptosis-related protein connections by the Naïve Bayesian model. Then, we identified some classical apoptotic PPIs and other previously unrecognized PPIs between apoptotic kinases, such as AMPK and ZIPK. Subsequently, we screened a series of candidate compounds targeting AMPK/ZIPK, synthesized some compounds and eventually discovered a novel dual-target activator (BL-AD008). Moreover, we found BL-AD008 bear remarkable anti-proliferative activities toward cervical cancer cells and could induce apoptosis by death-receptor and mitochondrial pathways. Additionally, we found that BL-AD008-induced apoptosis was affected by the combination of AMPK and ZIPK. Then, we found that BL-AD008 bear its anti-tumor activities and induced apoptosis by targeting AMPK/ZIPK in vivo. In conclusion, these results demonstrate the ability of systems biology network to identify some key apoptotic kinase targets AMPK and ZIPK; thus providing a dual-target small molecule activator (BL-AD008) as a potential new apoptosis-modulating drug in future cervical cancer therapy.