title: Melatonin antiproliferative effects require active mitochondrial function in embryonal carcinoma cells.
abstract: Although melatonin oncostatic and cytotoxic effects have been described in different types of cancer cells, the specific mechanisms leading to its antitumoral effects and their metabolic context specificity are still not completely understood. Here, we evaluated the effects of melatonin in P19 embryonal carcinoma stem cells (CSCs) and in their differentiated counterparts, cultured in either high glucose medium or in a galactose (glucose-free) medium which leads to glycolytic suppression and increased mitochondrial metabolism. We found that highly glycolytic P19 CSCs were less susceptible to melatonin antitumoral effects while cell populations relying on oxidative metabolism for ATP production were more affected. The observed antiproliferative action of melatonin was associated with an arrest at S-phase, decreased oxygen consumption, down-regulation of BCL-2 expression and an increase in oxidative stress culminating with caspase-3-independent cell death. Interestingly, the combined treatment of melatonin and dichloroacetate had a synergistic effect in cells grown in the galactose medium and resulted in an inhibitory effect in the highly resistant P19 CSCs. Melatonin appears to exert its antiproliferative activity in P19 carcinoma cells through a mitochondrially-mediated action which in turn allows the amplification of the effects of dichloroacetate, even in cells with a more glycolytic phenotype.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Rute
authors.initials: R
authors.lastname: Loureiro
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Silvia
authors.initials: S
authors.lastname: Magalhães-Novais
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Katia A
authors.initials: KA
authors.lastname: Mesquita
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|School of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Ines
authors.initials: I
authors.lastname: Baldeiras
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Isabel S
authors.initials: IS
authors.lastname: Sousa
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: Ludgero C
authors.initials: LC
authors.lastname: Tavares
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Ines A
authors.initials: IA
authors.lastname: Barbosa
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Paulo J
authors.initials: PJ
authors.lastname: Oliveira
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Department of Morphology and Cell Biology, University of Oviedo, Oviedo, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Vega-Naredo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054278:Embryonal Carcinoma Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008550:Melatonin
keywords: cancer stem cells; dichloroacetate; melatonin; metabolism; mitochondria