The long-term goal of this project is to identify novel redox base mechanisms that lead to the development of cancer. Our studies have identified the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) as an important regulator that can both modulate the development of cancer and be modulated during the progression of cancer. Our studies in the previous funding period demonstrate that reduction of MnSOD levels occurs very early in the development of skin cancer and that the level of p53 regulates the expression of MnSOD. We also found that the level of the mitochondrial uncoupling protein 1 (UCP1) is significantly increased in skin tissues of MnSOD-deficient mice. We hypothesize that the activities of p53, MnSOD and UCP1 are regulated to minimize reactive oxygen species (ROS) production in mitochondria. We propose that: 1) as a critical transcription factor, p53 cooperates with transcriptional activators and suppressors to regulate MnSOD transcription (Aim 1) and 2) the reduction of MnSOD levels in mitochondria leads to UCP1 induction as a result of compromised mitochondrial function, which induces transcriptional responses to reduce superoxide production from mitochondrial respiration (Aim 2). The positive and negative feedback loops between nuclei and mitochondria help to ensure that superoxide levels are minimized to prevent mitochondrial dysfunction and subsequent neoplastic transformation. We will use state-of-the-art molecular biology, biochemistry and free radical biology approaches to address these specific aims. Because mitochondria are major sites of cellular energy production and cellular ROS homeostasis, and are integrators of apoptosis signaling that are altered in cancer cells, understanding the regulation of mitochondrial ROS levels is important and will provide a unique opportunity to design novel interventions that maximize the benefits to normal tissues and prevent cancer development. Given that cellular redox status contributes to almost all aspects of biological function, and that MnSOD and p53 are critical for normal cellular function and for cancer prevention, the results from this study of cancer will have a broad impact on human health and the prevention of other diseases, including obesity and metabolic disorders.
Skin cancer is the most common human malignancy in the United States. Many chemicals and Ultraviolet radiation (UV) are well-established agents that cause skin cancer. We have found that the mitochondrial antioxidant enzyme manganese containing superoxide dismutase (MnSOD) is an important regulator that can modulate the development of cancer as well as be modulated during the progression of cancer. Our studies demonstrate that reduction of MnSOD levels occurs very early in the development of skin cancer and that expression of MnSOD is regulated by p53. We also found that the levels of the mitochondrial uncoupling protein (UCPs) are altered in skin tissue of MnSOD-deficient mice. In this application we will extend from this novel finding to determine how UCPs acts to prevent skin cancer and will perform proof-of-concept experiments to verify the feasibility of using the knowledge to be learned to prevent the development of skin cancer resulting from exposure to UV and/or alteration of mitochondrial function.
|Breckwoldt, Michael O; Pfister, Franz M J; Bradley, Peter M et al. (2014) Multiparametric optical analysis of mitochondrial redox signals during neuronal physiology and pathology in vivo. Nat Med 20:555-60|
|Zhao, Y; Miriyala, S; Miao, L et al. (2014) Redox proteomic identification of HNE-bound mitochondrial proteins in cardiac tissues reveals a systemic effect on energy metabolism after doxorubicin treatment. Free Radic Biol Med 72:55-65|
|Xu, Yong; Fang, Fang; Miriyala, Sumitra et al. (2013) KEAP1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells. Cancer Res 73:4406-17|
|Bakthavatchalu, V; Dey, S; Xu, Y et al. (2012) Manganese superoxide dismutase is a mitochondrial fidelity protein that protects Polýý against UV-induced inactivation. Oncogene 31:2129-39|
|Holley, Aaron K; Dhar, Sanjit Kumar; Xu, Yong et al. (2012) Manganese superoxide dismutase: beyond life and death. Amino Acids 42:139-58|
|Miao, Lu; St Clair, Daret K (2009) Regulation of superoxide dismutase genes: implications in disease. Free Radic Biol Med 47:344-56|
|Holley, Aaron K; St Clair, Daret K (2009) Watching the watcher: regulation of p53 by mitochondria. Future Oncol 5:117-30|
|Holley, Aaron K; St Clair, Daret K (2009) Preventing Dr. Jekyll from becoming Mr. Hyde: is manganese superoxide dismutase the key to prevent radiation-induced neoplastic transformation? Cancer Biol Ther 8:1972-3|
|Xu, Yong; Fang, Fang; Dhar, Sanjit K et al. (2008) Mutations in the SOD2 promoter reveal a molecular basis for an activating protein 2-dependent dysregulation of manganese superoxide dismutase expression in cancer cells. Mol Cancer Res 6:1881-93|
|Dey, Swatee; Bakthavatchalu, Vasudevan; Tseng, Michael T et al. (2008) Interactions between SIRT1 and AP-1 reveal a mechanistic insight into the growth promoting properties of alumina (Al2O3) nanoparticles in mouse skin epithelial cells. Carcinogenesis 29:1920-9|
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