Identification of a natural compound by cell-based screening that enhances interferon regulatory factor-1 activity and causes tumor suppression.
Identification of a natural compound by cell-based screening that enhances interferon regulatory factor-1 activity and causes tumor suppression.
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DOI：
10.1158/1535-7163.mct-11-0304
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发表时间：
2011-10
影响因子：
5.7
通讯作者：
Yim JH
中科院分区：
文献类型：
--
作者：
Gao J;Wang Y;Xing Q;Yan J;Senthil M;Akmal Y;Kowolik CM;Kang J;Lu DM;Zhao M;Lin Z;Cheng CH;Yip ML;Yim JH
转录因子干扰素调节因子-1(IRF-1)受多种肿瘤抑制刺激诱导，可介导肿瘤细胞的抗增殖和促凋亡作用。因此，寻找能够增强IRF-1活性的药物可能是癌症治疗的有效途径。开发了一种基于细胞的筛选试验，以利用依赖于IRF-1的荧光素酶报告细胞系来鉴定能够增强IRF-1活性的提取物和化合物。通过这种方法，我们鉴定了一种天然产物提取物和该提取物的已知活性成分黄芩素，它通过调节已知的IRF-1靶标PUMA和细胞周期蛋白D1，导致IRF-1依赖的报告基因表达和IRF-1蛋白显著增加。在低微摩尔范围内，黄芩素可抑制多种癌细胞株的体外生长。IRF-1在这种生长抑制中发挥了作用，在稳定转染针对IRF-1的shRNA的乳腺癌细胞系中，对生长抑制的显著抵抗证明了这一点。最后，在异种和同基因小鼠模型中，反复注射黄芩素可以抑制肿瘤的生长，而对动物没有毒性。这些发现表明，识别IRF-1活性增强子可能在抗癌治疗中有用，基于细胞的转录因子激活筛选可能是药物发现的有用方法。
The transcription factor interferon regulatory factor-1 (IRF-1) is induced by many tumor-suppressive stimuli and can mediate anti-proliferative and pro-apoptotic effects in cancer cells. Thus, identifying agents that enhance IRF-1 activity may be an effective approach to cancer therapy. A cell-based screening assay was developed to identify extracts and compounds that could enhance IRF-1 activity using an IRF-1-dependent luciferase reporter cell line. Through this approach, we identified a natural product extract and a known active component of this extract, baicalein, which causes a marked increase in IRF-1-dependent reporter gene expression and IRF-1 protein, with modulation of known IRF-1 targets PUMA and cyclin D1. Baicalein causes suppression of growth in vitro in multiple cancer cell lines in the low micromolar range. IRF-1 plays a role in this growth suppression as demonstrated by significant resistance to growth suppression in a breast cancer cell line stably transfected with shRNA against IRF-1. Finally, intraperitoneal baicalein by repeated injection causes inhibition of growth in both xenogeneic and syngeneic mouse models of cancer without toxicity to the animals. These findings indicate that identifying enhancers of IRF-1 activity may have utility in anticancer therapies, and that cell-based screening for activation of transcription factors can be a useful approach for drug discovery.