Identification of a novel small molecule HIF-1alpha translation inhibitor.
Identification of a novel small molecule HIF-1alpha translation inhibitor.
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DOI：
10.1158/1078-0432.ccr-08-3180
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发表时间：
2009-10-01
期刊：
影响因子：
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通讯作者：
Van Meir EG
中科院分区：
文献类型：
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作者：
Narita T;Yin S;Gelin CF;Moreno CS;Yepes M;Nicolaou KC;Van Meir EG
缺氧诱导因子-1（HIF-1）是细胞对低氧反应的中心介导物，并且作为提供对缺氧的适应性反应的广泛基因的转录因子起作用。HIF-1在肿瘤组织中过度表达，已成为实体瘤治疗的重要靶点。本研究鉴定了一种新的HIF-1α抑制剂，并探讨了其作用机制。使用基于HIF应答报告细胞的测定，筛选10，000元天然产物样化合物文库以鉴定新型HIF-1抑制剂。这使我们发现了KC 7 F2，一种以胱胺为中心结构的先导化合物。分析KC 7 F2对HIF-1转录、翻译和蛋白降解过程的影响。KC 7 F2显著抑制HIF介导的来自不同肿瘤类型的细胞中的转录，包括神经胶质瘤、乳腺癌和前列腺癌，并且在缺氧下表现出增强的细胞毒性。KC 7 F2阻止了HIF靶基因的激活，如碳酸酐酶IX、基质金属蛋白酶2（MMP 2）、内皮素1和烯醇化酶1。对KC 7 F2作用机制的研究表明，它通过下调HIF-1α蛋白的合成发挥作用，这种作用伴随着抑制真核翻译起始因子4 E结合蛋白1（4 EBP 1）和p70 S6激酶（S6 K）的磷酸化，这两种蛋白是HIF-1α蛋白合成的关键调节因子。这些结果表明，KC 7 F2是一种有效的HIF-1通路抑制剂，其作为癌症治疗剂的潜力值得进一步研究。
Hypoxia inducible factor-1 (HIF-1) is the central mediator of the cellular response to low oxygen and functions as a transcription factor for a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1 is over-expressed in cancer and has become an important therapeutic target in solid tumors. In this study, a novel HIF-1α inhibitor was identified and its molecular mechanism was investigated. Using a HIF-responsive reporter cell-based assay, a 10,000-membered natural product-like chemical compound library was screened to identify novel HIF-1 inhibitors. This led us to discover KC7F2, a lead compound with a central structure of cystamine. The effects of KC7F2 on HIF-1 transcription, translation and protein degradation processes were analyzed. KC7F2 markedly inhibited HIF-mediated transcription in cells derived from different tumor types, including glioma, breast and prostate cancers and exhibited enhanced cytotoxicity under hypoxia. KC7F2 prevented the activation of HIF-target genes such as Carbonic Anhydrase IX, Matrix Metalloproteinase 2 (MMP2), Endothelin 1 and Enolase 1. Investigation of the mechanism of action of KC7F2 showed that it worked through the down-regulation of HIF-1α protein synthesis, an effect accompanied by the suppression of the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and p70 S6 kinase (S6K), key regulators of HIF-1α protein synthesis. These results show that KC7F2 is a potent HIF-1 pathway inhibitor and that its potential as a cancer therapy agent warrants further study.