Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alterations in AP-1 and p53-mediated pathways in a skin cancer model

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Abstract
Previous studies in our laboratories demonstrated that overexpression of manganese superoxide dismutase (MnSOD) suppressed both the incidence and multiplicity of papillomas in a DMBA/TPA multi-stage skin carcinogenesis model. The activity of activator protein-1 (AP-1), which is associated with tumor promotion, was reduced in MnSOD transgenic mice overexpressing MnSOD in the skin, suggesting that MnSOD may reduce tumor incidence by suppressing AP-1 activation. In the present study, we report that reduction of MnSOD by heterozygous knockout of the MnSOD gene (Sod2 −/+, MnSOD KO) increased the levels of oxidative damage proteins and the activity of AP-1 following TPA treatment. RNA levels of ornithine decarboxylase (ODC) were also increased, suggesting an increase in cell proliferation in the KO mice. Histological examination confirmed that the number of proliferating cells in DMBA/TPA-treated mouse skin were higher in the KO mice. Interestingly, histological examination also demonstrated greater numbers of apoptotic cells in the KO mice after DMBA/TPA treatment. Evidence of apoptosis, including DNA fragmentation, cytochrome c release from mitochondria, and caspase 3 activation were also observed by biochemical assays of the skin tissues. Apoptosis was associated with an increase in nuclear levels of p53 as determined by Western analysis. Quantitative immunogold ultrastructural analysis confirmed that p53 immunoreactive protein levels were increased to a greater level in the nuclei of epidermal cells from MnSOD KO mice compared to epidermal nuclei from wild type mice similarly treated. Moreover, p53 levels further increased in the mitochondria of DMBA/TPA treated mice, and this increase was much greater in the MnSOD KO than in the wild type mice, suggesting a link between MnSOD deficiency and mitochondrial-mediated apoptosis. Pathological examination reveals no difference in the incidence and frequency of papillomas comparing the KO mice and their wild type littermates. Taken together, these results suggest that: (1) MnSOD deficiency enhanced TPA-induced oxidative stress and AP-1 and p53 levels, consistent with the increase in both proliferation and apoptosis events in the MnSOD KO mice, and (2) increased apoptosis may negate increased proliferation in the MnSOD deficient mice during an early stage of tumor development.

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