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 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 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 LTD 4.Results: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 Β-catenin or a constitutively active Β-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-B.Conclusions:The present novel data show that LTD 4, 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. © 2009 Cancer Research UK All rights reserved.