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首页> 外文期刊>Bioscience Reports >Bafilomycin A1 activates HIF-dependent signalling in human colon cancer cells via mitochondrial uncoupling
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Bafilomycin A1 activates HIF-dependent signalling in human colon cancer cells via mitochondrial uncoupling

机译:Bafilomycin A1通过线粒体解偶联激活人类结肠癌细胞中的HIF依赖性信号传导

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Mitochondrial uncoupling is implicated in many patho(physiological) states. Using confocal live cell imaging and an optical O2 sensing technique, we show that moderate uncoupling of the mitochondria with plecomacrolide Baf (bafilomycin A1) causes partial depolarization of the mitochondria and deep sustained deoxygenation of human colon cancer HCT116 cells subjected to 6% atmospheric O2. A decrease in iO2 (intracellular O2) to 0–10?μM, induced by Baf, is sufficient for stabilization of HIFs (hypoxia inducible factors) HIF-1α and HIF-2α, coupled with an increased expression of target genes including GLUT1 (glucose transporter 1), HIF PHD2 (prolyl hydroxylase domain 2) and CAIX (carbonic anhydrase IX). Under the same hypoxic conditions, treatment with Baf causes neither decrease in iO2 nor HIF-α stabilization in the low-respiring HCT116 cells deficient in COX (cytochrome c-oxidase). Both cell types?display equal capacities for HIF-α stabilization by hypoxia mimetics DMOG (dimethyloxalylglycine) and CoCl2, thus suggesting that the effect of Baf under hypoxia is driven mainly by mitochondrial respiration. Altogether, by activating HIF signalling under moderate hypoxia, mitochondrial uncoupling can play an important regulatory role in colon cancer metabolism and modulate adaptation of cancer cells to natural hypoxic environments.
机译:线粒体解偶联与许多病理(生理)状态有关。使用共聚焦活细胞成像和光学O2传感技术,我们显示线粒体与plecomacrolide Baf(bafilomycin A1)的适度解偶联会导致线粒体部分去极化,并使人类结肠癌HCT116细胞在6%的大气O2下深度持续脱氧。 Baf诱导的iO2(细胞内O2)降低至0–10?μM,足以稳定HIF(缺氧诱导因子)HIF-1α和HIF-2α,并增加包括GLUT1(葡萄糖)在内的靶基因的表达转运蛋白1),HIF PHD2(脯氨酰羟化酶结构域2)和CAIX(碳酸酐酶IX)。在相同的低氧条件下,用Baf进行处理不会导致COX(细胞色素c-氧化酶)缺乏的低呼吸HCT116细胞的iO2降低或HIF-α稳定。两种细胞都表现出相同的低氧模拟物DMOG(二甲基草酰甘氨酸)和CoCl2稳定HIF-α的能力,因此表明低氧条件下Baf的作用主要是由线粒体呼吸驱动的。总而言之,通过在中度低氧条件下激活HIF信号传导,线粒体解偶联可在结肠癌的新陈代谢中发挥重要的调节作用,并调节癌细胞对自然低氧环境的适应性。

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