Redox Regulation of Tumor Suppression by MnSOD

The overall goal of this research is to elucidate the mechanisms by which the mitochondrial antioxidant enzyme, manganese containing superoxide dismutase (MnSOD), modulates the carcinogenesis action of tumor promoters and UV radiation. Our studies in the previous funding period indicate that overexpression of MnSOD suppresses the incidence and multiplicity of papillomas in the 7-12-dimethylbenz (a) anthracene (DMBA)/ 12-O-tetradecanoylphorbol-1 3-acetate (TPA) multistage skin carcinogenesis model. MnSOD- mediated tumor suppression is, in part, mediated by reduction of AP-1 activation and expression of proliferation related genes. Unexpectedly, reduction of MnSOD by heterozygous knockout of the MnSOD gene does not result in increased tumor incidence or multiplicity using the DMBAITPA model. The lack of increased susceptibility to DMBAITPA-induced tumors in the MnSOD knockout mice is due, in part, to an increase in both apoptosis and proliferation after TPA treatment. Administration of MnSOD mimetic without interfering with TPA-induced apoptosis is very effective in reducing DMBAITPA-induced skin papillomas in MnSOD-deficient mice. We also found that the increased apoptosis in MnSOD-deficient mice is associated with increased p53 accumulation in the mitochondria and reduced MnSOD expression. Based upon these novel findings, we propose that activation of p53 enhances apoptosis, in part, via modulation of mitochondrial antioxidant defense capacity and that the tumor suppression effect of MnSOD is mediated, in part, by p53. Two specific aims are designed to test these hypotheses using TPA and UV radiation as the prototype oxidative stress generating carcinogens. The results of the proposed studies will provide insights into the common mechanisms by which MnSOD levels modulate apoptosis induced by chemical or UV radiation during an early stage of skin carcinogenesis. They will also enhance our understanding of the p53-dependent and -independent tumor suppression role of MnSOD. Identification of a common mechanism by which tumor promoter and UV radiation cause apoptosis would provide a means for developing a mechanistic based intervention that would prevent the development of skin cancers caused by a wide range of carcinogens. Thus, this timely and important study will likely have a large scale impact on human health.