title: Antioxidants can increase melanoma metastasis in mice.
abstract: Antioxidants in the diet and supplements are widely used to protect against cancer, but clinical trials with antioxidants do not support this concept. Some trials show that antioxidants actually increase cancer risk and a study in mice showed that antioxidants accelerate the progression of primary lung tumors. However, little is known about the impact of antioxidant supplementation on the progression of other types of cancer, including malignant melanoma. We show that administration of N-acetylcysteine (NAC) increases lymph node metastases in an endogenous mouse model of malignant melanoma but has no impact on the number and size of primary tumors. Similarly, NAC and the soluble vitamin E analog Trolox markedly increased the migration and invasive properties of human malignant melanoma cells but did not affect their proliferation. Both antioxidants increased the ratio between reduced and oxidized glutathione in melanoma cells and in lymph node metastases, and the increased migration depended on new glutathione synthesis. Furthermore, both NAC and Trolox increased the activation of the small guanosine triphosphatase (GTPase) RHOA, and blocking downstream RHOA signaling abolished antioxidant-induced migration. These results demonstrate that antioxidants and the glutathione system play a previously unappreciated role in malignant melanoma progression.
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, SE-405 30 Gothenburg, Sweden. Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Kristell
authors.initials: K
authors.lastname: Le Gal
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, SE-405 30 Gothenburg, Sweden. Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Mohamed X
authors.initials: MX
authors.lastname: Ibrahim
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, SE-405 30 Gothenburg, Sweden. Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Wiel
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden. Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Volkan I
authors.initials: VI
authors.lastname: Sayin
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, SE-405 30 Gothenburg, Sweden. Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Murali K
authors.initials: MK
authors.lastname: Akula
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, SE-405 30 Gothenburg, Sweden. Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Christin
authors.initials: C
authors.lastname: Karlsson
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, SE-405 30 Gothenburg, Sweden. Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Dalin
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Levent M
authors.initials: LM
authors.lastname: Akyürek
authors.affiliation: Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden. Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Lindahl
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, SE-405 30 Gothenburg, Sweden. Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, SE-405 30 Gothenburg, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Nilsson
authors.affiliation: Sahlgrenska Cancer Center, University of Gothenburg, SE-405 30 Gothenburg, Sweden. Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, SE-405 30 Gothenburg, Sweden. martin.bergo@gu.se.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
mesh_terms: D000111:Acetylcysteine / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000009:adverse effects / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002839:Chromans / Q000009:adverse effects / Q000494:pharmacology; D019587:Dietary Supplements / Q000009:adverse effects; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D008545:Melanoma / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology
chemical_list: D000975:Antioxidants; D002839:Chromans; D005978:Glutathione; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D000111:Acetylcysteine