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.
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|Wei, Xiaowei; Xu, Yong; Xu, Fang Fang et al. (2017) RelB Expression Determines the Differential Effects of Ascorbic Acid in Normal and Cancer Cells. Cancer Res 77:1345-1356|
|Miriyala, Sumitra; Thippakorn, Chadinee; Chaiswing, Luksana et al. (2016) Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress signaling. Free Radic Biol Med 91:68-80|
|Carroll, Dustin; Howard, Diana; Zhu, Haining et al. (2016) Simultaneous quantitation of oxidized and reduced glutathione via LC-MS/MS: An insight into the redox state of hematopoietic stem cells. Free Radic Biol Med 97:85-94|
|Keeney, Jeriel T R; Miriyala, Sumitra; Noel, Teresa et al. (2015) Superoxide induces protein oxidation in plasma and TNF-? elevation in macrophage culture: Insights into mechanisms of neurotoxicity following doxorubicin chemotherapy. Cancer Lett 367:157-61|
|Xu, Y; Miriyala, S; Fang, F et al. (2015) Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect. Oncogene 34:4229-37|
|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|
|Holley, Aaron K; Xu, Yong; Noel, Teresa et al. (2014) Manganese superoxide dismutase-mediated inside-out signaling in HaCaT human keratinocytes and SKH-1 mouse skin. Antioxid Redox Signal 20:2347-60|
|Dhar, Sanjit Kumar; Zhang, Jiayu; Gal, Jozsef et al. (2014) FUsed in sarcoma is a novel regulator of manganese superoxide dismutase gene transcription. Antioxid Redox Signal 20:1550-66|
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