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

BACKGROUND: Alteration in respiratory activity and mitochondrial DNA ( mtDNA) transcription seems to be an important feature of cancer cells. Leukotriene D-4 (LTD4) is a proinflammatory mediator implicated in the pathology of chronic inflammation and cancer. We have shown earlier that LTD4 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. 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) 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 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 beta-catenin or a constitutively active beta-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-kappa B. CONCLUSIONS: The present novel data show that LTD4, 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. British Journal of Cancer (2009) 101, 1596-1605. doi: 10.1038/sj.bjc.6605342 www.bjcancer.com Published online 13 October 2009 (C) 2009 Cancer Research UK