Mezhybovska M, Yudina Y, Abhyankar A, Sjölander A
Cell and Experimental Pathology, Department of Laboratory Medicine, Malmö University Hospital, Lund University, Malmö, SE-205 02, Sweden.
Br J Cancer. 2009 Nov 3;101(9):1596-605. doi: 10.1038/sj.bjc.6605342. Epub 2009 Oct 13.
Alteration in respiratory activity and mitochondrial DNA (mtDNA) transcription seems to be an important feature of cancer cells. Leukotriene D(4) (LTD(4)) is a proinflammatory mediator implicated in the pathology of chronic inflammation and cancer. We have shown earlier that LTD(4) causes translocation of beta-catenin both to the mitochondria, in which it associates with the survival protein Bcl-2 identifying a novel role for beta-catenin in cell survival, and to the nucleus in which it activates the TCF/LEF transcription machinery.
Here we have used non-transformed intestinal epithelial Int 407 cells and Caco-2 colon cancer cells, transfected or not with wild type and mutated (S33Y) beta-catenin to analyse its effect on mitochondria activity. We have measured the ATP/ADP ratio, and transcription of the mtDNA genes ND2, ND6 and 16 s in these cells stimulated or not with LTD(4).
We have shown for the first time that LTD(4) triggers a cellular increase in NADPH dehydrogenase activity and ATP/ADP ratio. In addition, LTD(4) significantly increased the transcription of mtDNA genes. Overexpression of wild-type beta-catenin or a constitutively active beta-catenin mutant mimicked the effect of LTD(4) on ATP/ADP ratio and mtDNA transcription. These elevations in mitochondrial activity resulted in increased reactive oxygen species levels and subsequent activations of the p65 subunit of NF-kappaB.
The present novel data show that LTD(4), presumably through beta-catenin accumulation in the mitochondria, affects mitochondrial activity, lending further credence to the idea that inflammatory signalling pathways are intrinsically linked with potential oncogenic signals.
呼吸活动和线粒体DNA（mtDNA）转录的改变似乎是癌细胞的一个重要特征。白三烯D4（LTD4）是一种促炎介质，与慢性炎症和癌症的病理过程有关。我们之前已经表明，LTD4会导致β-连环蛋白向线粒体转运，在那里它与存活蛋白Bcl-2结合，确定了β-连环蛋白在细胞存活中的新作用，同时也会导致β-连环蛋白向细胞核转运，在细胞核中它会激活TCF/LEF转录机制。
在这里，我们使用了未转化的肠上皮Int 407细胞和Caco-2结肠癌细胞，用野生型和突变型（S33Y）β-连环蛋白进行转染或未转染，以分析其对线粒体活性的影响。我们测量了这些细胞在有无LTD4刺激下的ATP/ADP比值以及mtDNA基因ND2、ND6和16 s的转录情况。
我们首次表明，LTD4会引发细胞中NADPH脱氢酶活性和ATP/ADP比值的增加。此外，LTD4显著增加了mtDNA基因的转录。野生型β-连环蛋白或组成型活性β-连环蛋白突变体的过表达模拟了LTD4对ATP/ADP比值和mtDNA转录的影响。线粒体活性的这些升高导致活性氧水平增加，随后NF-κB的p65亚基被激活。
目前的新数据表明，LTD4可能通过β-连环蛋白在线粒体中的积累影响线粒体活性，这进一步支持了炎症信号通路与潜在致癌信号内在相关的观点。
