title: Overexpression of manganese superoxide dismutase suppresses tumor formation by modulation of activator protein-1 signaling in a multistage skin carcinogenesis model.
abstract: Manganese superoxide dismutase (MnSOD) is a nuclear encoded primary antioxidant enzyme localized in mitochondria. Because expression of MnSOD plays a major role in maintaining cellular redox status and reactive oxygen species are known to play a role in signal transduction and carcinogenesis, we investigated the role of MnSOD in the development of cancer using a two-stage [7,12-dimethylbenz(a)-anthracene plus 12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis model. Female transgenic mice expressing the human MnSOD gene in the skin and their nontransgenic counterparts were used in this study. Pathological examination demonstrated significant reduction of papilloma formation in transgenic mice. Quantitative analysis of 4-hydroxy-2-nonenal-modified proteins showed greater accumulation of oxidative damage products in nontransgenic compared with transgenic mice, and this oxidative damage was demonstrated to be present in both mitochondria and nucleus. TPA increased activator protein-1 (AP-1) binding activity within 6 h in nontransgenic mice, but increased AP-1 binding activity was delayed in the transgenic mice. Electrophoretic mobility shift assay, transcription of the target genes, and Western analysis studies indicated that the increased AP-1 binding activity was attributable to induction of the Jun but not the Fos protein families. Overexpression of MnSOD selectively inhibited the TPA-induced activation of protein kinase Cepsilon and prevented subsequent activation of c-Jun NH(2)-terminal kinase in response to TPA. Overall, these results indicate that MnSOD regulates both cellular redox status and selectively modulates PKCepsilon signaling, thereby delaying AP-1 activation and inhibiting tumor promotion, resulting in reduction of tumors in MnSOD transgenic mice.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: Y
authors.initials: Y
authors.lastname: Xue
authors.forename: T D
authors.initials: TD
authors.lastname: Oberley
authors.forename: K K
authors.initials: KK
authors.lastname: Kiningham
authors.forename: S M
authors.initials: SM
authors.lastname: Lin
authors.forename: H C
authors.initials: HC
authors.lastname: Yen
authors.forename: H
authors.initials: H
authors.lastname: Majima
authors.forename: J
authors.initials: J
authors.lastname: Hines
authors.forename: D
authors.initials: D
authors.lastname: St  Clair
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000633:toxicity; D018808:Transcription Factor AP-1 / Q000378:metabolism / Q000502:physiology*
chemical_list: D002273:Carcinogens; D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D015127:9,10-Dimethyl-1,2-benzanthracene; D013482:Superoxide Dismutase; C497256:Prkce protein, mouse; C497255:PRKCE protein, human; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate