title: Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis.
abstract: To support growth, tumour cells reprogramme their metabolism to simultaneously upregulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling.
authors: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.|Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: Sara M
authors: SM
authors: Nowinski
authors: Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.|Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: Ashley
authors: A
authors: Solmonson
authors: Science Park Research Division, University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA.
authors: Joyce E
authors: JE
authors: Rundhaug
authors: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: Okkyung
authors: O
authors: Rho
authors: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: Jiyoon
authors: J
authors: Cho
authors: Center for Molecular Medicine, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Cory U
authors: CU
authors: Lago
authors: Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: Christopher L
authors: CL
authors: Riley
authors: Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: Sunhee
authors: S
authors: Lee
authors: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: Shohei
authors: S
authors: Kohno
authors: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: Christine K
authors: CK
authors: Dao
authors: Department of Nutritional Physiology, Institute of Health Biosciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
authors: Takeshi
authors: T
authors: Nikawa
authors: Science Park Research Division, University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA.
authors: Shawn B
authors: SB
authors: Bratton
authors: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.|Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: Casey W
authors: CW
authors: Wright
authors: Science Park Research Division, University of Texas MD Anderson Cancer Center, Smithville, Texas 78957, USA.
authors: Susan M
authors: SM
authors: Fischer
authors: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.|Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: John
authors: J
authors: DiGiovanni
authors: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.|Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, USA.|Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
authors: Edward M
authors: EM
authors: Mills
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000235:genetics; D005434:Flow Cytometry; D063990:Gene Ontology; D006801:Humans; D015151:Immunoblotting; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics*; D055442:Metabolome; D055432:Metabolomics; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009374:Neoplasms, Experimental; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D000071247:Uncoupling Protein 3
chemical_list: D002273:Carcinogens; D007473:Ion Channels; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C000604392:UCP3 protein, human; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D051057:Proto-Oncogene Proteins c-akt; D013755:Tetradecanoylphorbol Acetate