Abstract 1606: Altered regulation of manganese superoxide dismutase is an important pre-carcinogenesis event mediated by p53

Abstract

Abstract Cancer cells have aberrant manganese superoxide dismutase (MnSOD) activity and MnSOD deficient mice exhibit abnormal mitochondrial pathology. Recent data from human and animal studies indicate that the activity of MnSOD and the tumor suppressor gene, p53, are important for the maintenance of cellular energy metabolism. In addition, these critical proteins regulate oxidative stress to control the switch from oxidative phosphorylation to the aerobic glycolysis that is observed in cancer cells (Warburg's effect). It has been well-documented that MnSOD level is reduced in transformed cells and benign cancer tissues but increased in some aggressive cancers. However, there is little information concerning the regulation of MnSOD during carcinogenesis in vivo. Furthermore, when and how the alteration of MnSOD transcription occurs during the process of tumor development is unclear. To address these questions, we employed three complementary approaches in vitro and in vivo. First, we generated transgenic mice expressing luciferase reporter gene under the control of human MnSOD promoter/enhancer elements for investigating changes in MnSOD expression in animals by a non-invasive in vivo imaging. Second we used the 7-12-dimethylbenz(a)anthracene (DMBA)/TPA treated multistage skin carcinogenesis model to generate tumors and identify transcription factors associated with the expression of MnSOD in pathologically normal-appearing skin tissue, papillomas and squamous cell carcinoma. Third, we used Chromatin-immunoprecipation, EMSA, RNAi mediated knock-down and over-expression of candidates transcription factors in cultured cells to verify their roles in regulation of MnSOD at each stage of cancer development. The results demonstrate that reduction of MnSOD occurred very early in the carcinogenesis process and preceded the formation of any detectable tumor. The reduction of MnSOD transcription continued until papillomas were detected. However, as the benign tumor progressed into carcinoma, MnSOD expression was drastically increased. Contributing factors leading to the suppression and de-repression of MnSOD expression included Sp1, members of the NF-κB family, and p53. Among these important transcription factors, p53 appeared to play a major role in the switch from suppressed expression of MnSOD in the early carcinogenesis process to overexpression of MnSOD at late stages of cancer development. These results have identified MnSOD as a p53 regulated gene during cancer development and progression and highlighted the importance of mitochondrial oxidative stress in carcinogenesis at the early stages and chemo- and radio-resistance at the late stages of cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1606. doi:10.1158/1538-7445.AM2011-1606