Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-alpha transgenic mouse model of liver cancer.
OBJECTIVE
Co-expression of c-Myc and TGF-alpha in the mouse liver accelerates hepatocarcinogenesis and enhances DNA damage due to chronic oxidative stress. Dietary supplementation with vitamin E (VE) inhibits hepatocarcinogenesis and reduces chromosomal alterations in the same mice. Here we investigated the sources of reactive oxygen species (ROS) production in c-Myc/TGF-alpha transgenic mice.


METHODS
Inducible nitric oxide synthase (iNOS) and NADPH oxidase levels were determined in c-Myc, TGF-alpha and c-Myc/TGF-alpha mice by RT-PCR, western blot analysis and immunohistochemistry.


RESULTS
iNOS and nitrotyrosines levels were higher in the three transgenic lines when compared with wild-type mice. Preneoplastic and neoplastic lesions from c-Myc, TGF-alpha and c-Myc/TGF-alpha transgenic mice displayed upregulation of NADPH oxidase subunits p47-, 67-phox, Rac1, HSP 70, and HO-1. Importantly, dietary supplementation with vitamin E abolished iNOS expression, lowered nitrotyrosines, p47-, p67-phox, and Rac1 levels, and suppressed HSP 70 and HO-1 proteins in c-Myc/TGF-alpha livers.


CONCLUSIONS
The results suggest that iNOS and NADPH oxidase are involved in ROS generation during c-Myc/TGF-alpha hepatocarcinogenesis and are inhibited by VE treatment. The data provide additional evidence for the potential use of VE in treatment of chronic liver diseases and HCC prevention.
Calvisi
Diego F
DF
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 4146A1, 37 Convent Drive MSC 4262, Bethesda, MD 20892-4258, USA.
Ladu
Sara
S
Hironaka
Koji
K
Factor
Valentina M
VM
Thorgeirsson
Snorri S
SS
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology*
D000975:Antioxidants; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; D016271:Proto-Oncogene Proteins c-myc; D016211:Transforming Growth Factor alpha; D014810:Vitamin E; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019255:NADPH Oxidases