title: The role of thioredoxin reductase 1 in melanoma metabolism and metastasis.
abstract: Although significant progress has been made in targeted and immunologic therapeutics for melanoma, many tumors fail to respond, and most eventually progress when treated with the most efficacious targeted combination therapies thus far identified. Therefore, alternative approaches that exploit distinct melanoma phenotypes are necessary to develop new approaches for therapeutic intervention. Tissue microarrays containing human nevi and melanomas were used to evaluate levels of the antioxidant protein thioredoxin reductase 1 (TR1), which was found to increase as a function of disease progression. Melanoma cell lines revealed metabolic differences that correlated with TR1 levels. We used this new insight to design a model treatment strategy that creates a synthetic lethal interaction wherein targeting TR1 sensitizes melanoma to inhibition of glycolytic metabolism, resulting in a decrease in metastases in vivo. This approach holds the promise of a new clinical therapeutic strategy, distinct from oncoprotein inhibition.
authors.affiliation: Department of Dermatology, Oregon Health & Science University, Portland, OH, USA.
authors.forename: Pamela B
authors.initials: PB
authors.lastname: Cassidy
authors.affiliation: Department of Dermatology, Oregon Health & Science University, Portland, OH, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Honeggar
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Poerschke
authors.affiliation: Department of Dermatology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: White
authors.affiliation: Department of Dermatology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Florell
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Robert H I
authors.initials: RH
authors.lastname: Andtbacka
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors.forename: Joycelyn
authors.initials: J
authors.lastname: Tross
authors.affiliation: Department of Dermatology, Oregon Health & Science University, Portland, OH, USA.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Anderson
authors.affiliation: Department of Dermatology, Oregon Health & Science University, Portland, OH, USA.
authors.forename: Sancy A
authors.initials: SA
authors.lastname: Leachman
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Moos
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006019:Glycolysis; D006801:Humans; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D054481:Thioredoxin Reductase 1 / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D054481:Thioredoxin Reductase 1
keywords: immunohistochemistry; melanoma; metabolism; mitochondria; thioredoxinreductase