Mechanistic Studies of a Dietary Combination in Cancer Prevention: The Effects of MnSOD on Tumor Suppressor Gene Activation

Reactive oxygen species can act as signaling transduction molecules modulating various pathways, such as the PI3K/Akt pathway. It is known that this pathway is constitutively activated in tumorigenesis contributing to protein synthesis, cell cycle progression, migration and survival. However, the PI3K/Akt pathway is negatively regulated by the major tumor suppressor protein PTEN. PTEN has dual specificity phosphatase activity regulating Akt phosphorylation as a lipid phosphatase; as well as, regulating cyclin D1 expression as a protein phosphotase. However, these are the roles of cytoplasmic PTEN. Recently, the nuclear roles of PTEN have received significant attention. Nuclear PTEN plays a major role in maintaining cellular homeostasis and stability by contributing to chromosome stability, DNA repair and cell cycle arrest. Previous studies have shown that PTEN nuclear localization is mediated by oxidative stress and may play a role in p53 stabilization. Nevertheless, MnSOD is considered to be a novel tumor suppressor gene. MnSOD has been defined as a nuclear encoded primary antioxidant enzyme localized in the mitochondria. We have shown in previous studies that the dietary combination Protandim reduced tumor incidence and multiplicity via the synergistic induction of superoxide dismutase enzymes. It has been shown that overexpression of MnSOD in in vivo models can suppress tumor formation via modulation of AP-1 binding. Therefore, it is imperative to look at how MnSOD may affect the process of apoptosis and the activation of tumor suppressor genes involved (i.e. PTEN and p53). Using our in vivo models (wildtype, MnSOD knockout, non-transgenic and MnSOD transgenic mice), we investigated how modulation of MnSOD expression may affect PTEN-mediated p53 stabilization, and how this contributes to chemoprevention. In addition, we explored how mutations in p53 may affect the PTEN-p53 interaction and its effects on tumor promotion via a gene transfection approach.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 965.