title: Tamoxifen enhancement of TNF-alpha induced MnSOD expression: modulation of NF-kappaB dimerization.
abstract: Manganese superoxide dismutase (MnSOD) has been shown to suppress the development of cancer. Tamoxifen (TAM), a nonsteroidal anti-estrogen that is widely used in chemotherapy, is known to be a modulator of antioxidant status. However, the mechanism by which TAM mediates antioxidant enzyme induction remains unclear. In this study we investigated TAM enhancement of MnSOD induction by TNF-alpha. The results show that co-treatment with TAM and TNF-alpha increases the MnSOD promoter/enhancer driven luciferase activity, MnSOD mRNA and protein levels. Interestingly, co-treatment with TAM and TNF-alpha drastically decreases the binding activity of the p50/p50 homodimer and increases that of the p50/p65 heterodimer compared to TNF-alpha alone. This change in DNA binding could not be attributed to a decrease in the level of p50, its precursor, p105, or its inhibitors. Furthermore, TAM did not enhance degradation of IkappaB-alpha. These results suggest that p50/p50 homodimer may act as an inhibitory complex of MnSOD expression. Modulation of the DNA binding activity in favor of the p50/p65 complex may enhance NF-kappaB mediated induction of MnSOD by TAM. These findings reveal a potential novel mechanism for the induction of the human MnSOD gene.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky, KY 40536, USA.
authors.forename: Chotiros
authors.initials: C
authors.lastname: Daosukho
authors.forename: Kelley
authors.initials: K
authors.lastname: Kiningham
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kasarskis
authors.forename: Wanida
authors.initials: W
authors.lastname: Ittarat
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002460:Cell Line; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003840:Deoxycholic Acid / Q000494:pharmacology; D019281:Dimerization; D004357:Drug Synergism; D004742:Enhancer Elements, Genetic; D004965:Estrogen Antagonists / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D020672:I-kappa B Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D003840:Deoxycholic Acid; D013629:Tamoxifen; D000072000:NF-KappaB Inhibitor alpha; C016601:afimoxifene; D013482:Superoxide Dismutase