Targeting the hypoxia inducible factor pathway with mitochondrial uncouplers
Targeting the hypoxia inducible factor pathway with mitochondrial uncouplers
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DOI：
10.1007/s11010-006-9295-3
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发表时间：
2007-02-01
影响因子：
4.3
通讯作者：
Kim, Myoung H.
中科院分区：
文献类型：
--
作者：
Thomas, Rusha;Kim, Myoung H.
缺氧诱导因子-1（HIF-1）是肿瘤对缺氧的大多数适应性反应的中心，并且由缺氧诱导的HIF-1 α或-2 α亚基和组成性表达的HIF-1 β亚基组成。以前，线粒体解偶联剂，rottlerin和FCCP，被证明可以增加细胞的O-2消耗率。在这项研究中，我们确定了线粒体解偶联剂，rottlerin和FCCP，显着降低缺氧以及常氧HIF-1转录活性，这是部分介导的氧不稳定的HIF-1 α和HIF-2 α蛋白水平在PC-3和DU-145前列腺癌细胞的下调。我们的研究结果还表明，线粒体解偶联剂降低HIF靶基因，VEGF和VEGF受体-2的表达。总之，我们的研究结果表明，功能性线粒体是重要的HIF-1 α和HIF-2 α蛋白的稳定性和转录活性在常氧以及缺氧，线粒体解偶联剂可能是有用的抑制肿瘤中的HIF途径。
Hypoxia inducible factor-1 (HIF-1) is central to most adaptation responses of tumors to hypoxia, and consists of a hypoxia inducible HIF-1 alpha or -2 alpha subunit, and a constitutively expressed HIF-1 beta subunit. Previously, mitochondrial uncouplers, rottlerin and FCCP, were shown to increase the rate of cellular O-2 consumption. In this study, we determined that mitochondrial uncouplers, rottlerin and FCCP, significantly decreased hypoxic as well as normoxic HIF-1 transcriptional activity which was in part mediated by down-regulation of the oxygen labile HIF-1 alpha and HIF-2 alpha protein levels in PC-3 and DU-145 prostate cancer cells. Our results also revealed that mitochondrial uncouplers decreased the expression of HIF target genes, VEGF and VEGF receptor-2. Taken together, our results indicate that functional mitochondria are important in HIF-1 alpha and HIF-2 alpha protein stability and transcriptional activity during normoxia as well as in hypoxia, and that mitochondrial uncouplers may be useful in the inhibition of HIF pathway in tumors.