β-Catenin is involved in alterations in mitochondrial activity in non-transformed intestinal epithelial and colon cancer cells

Abstract

Background:Alteration in respiratory activity and mitochondrial DNA (mtDNA) transcription seems to be an important feature of cancer cells. Leukotriene D4 (LTD4) is a proinflammatory mediator implicated in the pathology of chronic inflammation and cancer. We have shown earlier that LTD4 causes translocation of β-catenin both to the mitochondria, in which it associates with the survival protein Bcl-2 identifying a novel role for β-catenin in cell survival, and to the nucleus in which it activates the TCF/LEF transcription machinery.Methods: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) β-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 LTD4.Results:We have shown for the first time that LTD4 triggers a cellular increase in NADPH dehydrogenase activity and ATP/ADP ratio. In addition, LTD4 significantly increased the transcription of mtDNA genes. Overexpression of wild-type β-catenin or a constitutively active β-catenin mutant mimicked the effect of LTD4 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-κB.Conclusions:The present novel data show that LTD4, presumably through β-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.