Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-κB activation and oxidative stress

Zoltán Derdák, Péter Fülöp, Edmond Sabo, Rose Tavares, Eric P. Berthiaume, Murray B. Resnick, György Paragh, Jack R. Wands, György Baffy

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Abstract

Oxidative stress has a complex effect on cancer development. To further study this process, we induced colon tumors with azoxymethane (AOM) in mice deficient for uncoupling protein-2 (UCP2). UCP2 has recently emerged as a negative regulator of mitochondrial oxidant production. When overexpressed, UCP2 protects cells from oxidative stress, while its absence may cause abundance of reactive oxygen species, release of pro-inflammatory cytokines and persistent activation of nuclear factor kappaB (NF-κB), a pleiotropic transcription factor with an increasingly recognized role in cancer. Here we show that Ucp2-/- mice develop more aberrant crypt foci and colon tumors than Ucp2+/+ littermates when examined 24 weeks after the completion of treatment with AOM (10 mg/kg i.p. weekly for a total of 6 weeks, n = 8-12). This effect is primarily seen in the proximal colon of Ucp2-/- mice (P < 0.05), in association with changes indicative of increased oxidative stress (increased staining for malondialdehyde and inducible nitric oxide synthase), enhanced NF-κB activation (increased levels of phosphorylated IκB and increased nuclear presence of p65) and a disrupted balance between intestinal epithelial cell proliferation (greater 5-bromo-2′-deoxy- uridine incorporation rates and increased phosphorylation of ERK1/2 and AKT) and apoptosis (decreased number of terminal deoxynucleotidyltransferase-mediated nick-end-labeling (TUNEL)-positive cells and increased expression of Bcl-2). In conclusion, our findings provide the first in vivo evidence for a link between UCP2 and tumorigenesis and indicate the need for additional studies to assess the role of mitochondrial uncoupling in cancer development.

Original languageEnglish
Pages (from-to)956-961
Number of pages6
JournalCarcinogenesis
Volume27
Issue number5
DOIs
Publication statusPublished - May 1 2006

ASJC Scopus subject areas

  • Cancer Research

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    Derdák, Z., Fülöp, P., Sabo, E., Tavares, R., Berthiaume, E. P., Resnick, M. B., Paragh, G., Wands, J. R., & Baffy, G. (2006). Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-κB activation and oxidative stress. Carcinogenesis, 27(5), 956-961. https://doi.org/10.1093/carcin/bgi335