Irigenin, a novel lead from Western Himalayan chemiome inhibits Fibronectin-Extra Domain A induced metastasis in Lung cancer cells.
Irigenin, a novel lead from Western Himalayan chemiome inhibits Fibronectin-Extra Domain A induced metastasis in Lung cancer cells.
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irigenin是来自西马拉扬西部化学组的新型铅，抑制纤连蛋白 - 脱发结构域在肺癌细胞中诱导的转移。
DOI：
10.1038/srep37151
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发表时间：
2016-11-16
影响因子：
4.6
通讯作者：
Qadri RA
中科院分区：
文献类型：
--
作者：
Amin A;Chikan NA;Mokhdomi TA;Bukhari S;Koul AM;Shah BA;Gharemirshamlu FR;Wafai AH;Qadri A;Qadri RA
几条证据表明纤连蛋白额外结构域A（EDA）通过接合细胞表面α9β1整联蛋白来促进肿瘤细胞的转移能力。这种由EDA的C-C环介导的相互作用激活了导致肿瘤细胞上皮向间质转化（EMT）的原癌信号通路，从而表明其在控制转移进展中的重要性。在此背景下，本研究的目的是探索活性化合物从选定的民族药用植物的西喜马拉雅地区的肺癌细胞中靶向EDA纤连蛋白。采用用于药物设计和筛选的基于结构的信息学来产生构象上和能量上可行的先导化合物进料。在所筛选的120个化合物中，鸢尾苷元与EDA的C-C环的结合能力最强。鸢尾苷元特异性靶向EDA上的α9β1和α4β1整联蛋白结合位点，所述EDA在其C-C环中包含LEU 46、PHE 47、PRO48、GLU 58、LEU 59和GLN 60，如通过鸢尾苷元-EDA复合物的每个残基的能量分解所评价的。体外细胞运动性测定与EDA敲入和敲低测定互补，明确证明鸢尾苷元通过选择性阻断EDA来防止肺癌细胞的转移能力。因此，所呈现的结果表明鸢尾苷元作为先导化合物来克服纤连蛋白EDA诱导的肺癌细胞中的转移进展。
Several lines of evidence indicate that Fibronectin Extra Domain A (EDA) promotes metastatic capacity of tumor cells by engaging cell surface α9β1 integrins. This interaction mediated by the C-C loop of EDA activates pro-oncogenic signaling pathways leading to epithelial to mesenchymal transition (EMT) of tumor cells, thus signifying its importance in control of metastatic progression. In this context the present study was designed to explore the active compounds from selected ethno-medicinal plants of western Himalayan region for targeting EDA of Fibronectin in lung carcinoma cells. Structure based informatics for drug designing and screening was employed to generate a lead compound(s) feed that were conformationally and energetically viable. Out of 120 compounds selected, Irigenin showed best binding-affinity with C-C loop of EDA. Irigenin specifically targeted α9β1 and α4β1 integrin binding sites on EDA comprising LEU46, PHE47, PRO48, GLU58, LEU59 and GLN60 in its C-C loop as evaluated by energy decomposition per residue of Irigenin–EDA complex. In-vitro cell motility assays complemented with EDA knock-in and knockdown assays distinctively demonstrated that Irigenin prevents metastatic capacity of lung cancer cells by selectively blocking EDA. The results presented thus project Irigenin as a lead compound to overcome Fibronectin EDA induced metastatic progression in lung carcinoma cells.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
6.1
作者：
Ahn, KS;Noh, EJ;Jung, SH
通讯作者：
Jung, SH
影响因子：
4.4
作者：
Amin, Asif;Mokhdomi, Taseem A.;Qadri, Raies A.
通讯作者：
Qadri, Raies A.
影响因子：
3
作者：
Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG