Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-kappaB activation and oxidative stress.
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-kappaB), 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-kappaB activation (increased levels of phosphorylated IkappaB 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.
Derdák
Zoltán
Z
Division of Gastroenterology and Liver Research Center, Brown Medical School and Rhode Island Hospital, Providence, RI 02903, USA.
Fülöp
Péter
P
Sabo
Edmond
E
Tavares
Rose
R
Berthiaume
Eric P
EP
Resnick
Murray B
MB
Paragh
György
G
Wands
Jack R
JR
Baffy
György
G
D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D020287:In Situ Nick-End Labeling; D007473:Ion Channels; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics* / Q000502:physiology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D013997:Time Factors; D000071246:Uncoupling Protein 2
D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2