Journal Article

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 and György Baffy

in Carcinogenesis

Volume 27, issue 5, pages 956-961
Published in print May 2006 | ISSN: 0143-3334
Published online January 2006 | e-ISSN: 1460-2180 | DOI: https://dx.doi.org/10.1093/carcin/bgi335

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

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.

Keywords: ACF, aberrant crypt foci; AOM, azoxymethane; BrdU, 5-bromo-2′-deoxy-uridine; iNOS, inducible nitric oxide synthase; IOD, integrated optical density; MDA, malondialdehyde; NF-κB, nuclear factor kappaB; ROS, Reactive oxygen species; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling; UCP2, uncoupling protein-2

Journal Article.  4010 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.