Beta-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) (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.


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 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 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.


CONCLUSIONS
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.
Mezhybovska
M
M
Cell and Experimental Pathology, Department of Laboratory Medicine, Malmö University Hospital, Lund University, Malmö, SE-205 02, Sweden.
Yudina
Y
Y
Abhyankar
A
A
Sjölander
A
A
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D017998:Leukotriene D4 / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051176:beta Catenin / Q000502:physiology*
C495270:CTNNB1 protein, human; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051176:beta Catenin; D000244:Adenosine Diphosphate; D017998:Leukotriene D4; D000255:Adenosine Triphosphate