title: Enhanced OXPHOS, glutaminolysis and β-oxidation constitute the metastatic phenotype of melanoma cells.
abstract: Tumours display different cell populations with distinct metabolic phenotypes. Thus, subpopulations can adjust to different environments, particularly with regard to oxygen and nutrient availability. Our results indicate that progression to metastasis requires mitochondrial function. Our research, centered on cell lines that display increasing degrees of malignancy, focused on metabolic events, especially those involving mitochondria, which could reveal which stages are mechanistically associated with metastasis. Melanocytes were subjected to several cycles of adhesion impairment, producing stable cell lines exhibiting phenotypes representing a progression from non-tumorigenic to metastatic cells. Metastatic cells (4C11+) released the highest amounts of lactate, part of which was derived from glutamine catabolism. The 4C11+ cells also displayed an increased oxidative metabolism, accompanied by enhanced rates of oxygen consumption coupled to ATP synthesis. Enhanced mitochondrial function could not be explained by an increase in mitochondrial content or mitochondrial biogenesis. Furthermore, 4C11+ cells had a higher ATP content, and increased succinate oxidation (complex II activity) and fatty acid oxidation. In addition, 4C11+ cells exhibited a 2-fold increase in mitochondrial membrane potential (ΔΨmit). Consistently, functional assays showed that the migration of cells depended on glutaminase activity. Metabolomic analysis revealed that 4C11+ cells could be grouped as a subpopulation with a profile that was quite distinct from the other cells investigated in the present study. The results presented here have centred on how the multiple metabolic inputs of tumour cells may converge to compose the so-called metastatic phenotype.
authors.affiliation: Instituto de Bioquímica Médica Leopoldo De Meis, Universidade Federal do RIo de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Mariana F
authors.initials: MF
authors.lastname: Rodrigues
authors.affiliation: Maladies Rares: Génétique et Métabolisme, Université de Bordeaux Segalen, Bordeaux, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Obre
authors.affiliation: Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, Brazil Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, Brazil.
authors.forename: Fabiana H M
authors.initials: FH
authors.lastname: de Melo
authors.affiliation: Instituto de Bioquímica Médica Leopoldo De Meis, Universidade Federal do RIo de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Gilson C
authors.initials: GC
authors.lastname: Santos
authors.affiliation: Instituto de Bioquímica Médica Leopoldo De Meis, Universidade Federal do RIo de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Antonio
authors.initials: A
authors.lastname: Galina
authors.affiliation: Departamento de Farmacologia, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Miriam G
authors.initials: MG
authors.lastname: Jasiulionis
authors.affiliation: Maladies Rares: Génétique et Métabolisme, Université de Bordeaux Segalen, Bordeaux, France.
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Rossignol
authors.affiliation: Instituto de Bioquímica Médica Leopoldo De Meis, Universidade Federal do RIo de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Franklin D
authors.initials: FD
authors.lastname: Rumjanek
authors.affiliation: Instituto de Bioquímica Médica Leopoldo De Meis, Universidade Federal do RIo de Janeiro, Rio de Janeiro, Brazil amoedo@bioqmed.ufrj.br.
authors.forename: Nivea D
authors.initials: ND
authors.lastname: Amoêdo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D005947:Glucose / Q000378:metabolism; D005972:Glutaminase / Q000378:metabolism; D005973:Glutamine / Q000235:genetics / Q000378:metabolism*; D007773:Lactates / Q000378:metabolism; D008544:Melanocytes / Q000473:pathology / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008564:Membrane Potentials / Q000502:physiology; D008660:Metabolism; D051379:Mice; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000502:physiology*; D010641:Phenotype
chemical_list: D007773:Lactates; D005973:Glutamine; D005972:Glutaminase; D005947:Glucose
keywords: OXPHOS; energy metabolism; metastasis; mitochondrial physiology