Abstract
Abstract Metabolic reprogramming is a hallmark of tumorigenesis and malignancy across a variety of cancer types. Reduced oxidative phosphorylation and increased ATP synthesis by glycolytic upregulation is thought to provide both the energy and metabolic precursors necessary to meet the increased biosynthetic and energetic demands associated with malignancy. We hypothesized that since uncoupling protein 3 (UCP3) dissipates the mitochondrial electrochemical proton gradient, it may lead to the consumption or depletion of biosynthetic substrates necessary for carcinogenesis. In support, previous studies have shown that mice expressing a keratin 5-UCP3 transgene are completely resistant to chemically- and Ras-induced skin carcinogenesis, however the metabolic consequences of UCP3 overexpression in relation to cancer resistance are unclear. To examine the metabolic changes associated with UCP3 expression and this profound skin cancer resistance, we performed metabolomic analysis of more than 350 metabolites in epidermis from K5-UCP3 and wild type FVB/N littermate mice. Results of this analysis show significant UCP3-dependent changes in metabolites indicative of increased energy harvesting via glycolysis, beta-oxidation and branched chain amino acid metabolism. Consistent with decreased energy reserve, K5-UCP3 epidermis exhibits increased uncoupled respiration, decreased ATP and increased AMP levels, which correspond to increased AMP Kinase (AMPK) activation (Thr172 phosphorylation). Taken together, these data suggest that uncoupling proteins might function to oppose the metabolic demands of tumorigenesis and suggest that targeting mitochondrial uncoupling may be a novel and effective strategy in cancer prevention and treatment. Citation Format: Ashley Solmonson, Mignon Keaton, Sara M. Nowinski, Elizabeth Morin-Kensicki, Edward M. Mills. Metabolomic analysis provides insights into uncoupling-induced cancer resistance in the K5-UCP3 mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1888. doi:10.1158/1538-7445.AM2013-1888
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