title: Melatonin Cytotoxicity Is Associated to Warburg Effect Inhibition in Ewing Sarcoma Cells.
abstract: Melatonin kills or inhibits the proliferation of different cancer cell types, and this is associated with an increase or a decrease in reactive oxygen species, respectively. Intracellular oxidants originate mainly from oxidative metabolism, and cancer cells frequently show alterations in this metabolic pathway, such as the Warburg effect (aerobic glycolysis). Thus, we hypothesized that melatonin could also regulate differentially oxidative metabolism in cells where it is cytotoxic (Ewing sarcoma cells) and in cells where it inhibits proliferation (chondrosarcoma cells). Ewing sarcoma cells but not chondrosarcoma cells showed a metabolic profile consistent with aerobic glycolysis, i.e. increased glucose uptake, LDH activity, lactate production and HIF-1α activation. Melatonin reversed Ewing sarcoma metabolic profile and this effect was associated with its cytotoxicity. The differential regulation of metabolism by melatonin could explain why the hormone is harmless for a wide spectrum of normal and only a few tumoral cells, while it kills specific tumor cell types.
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, c/Julian Claveria, 33006 Oviedo, University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sanchez-Sanchez
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, c/Julian Claveria, 33006 Oviedo, University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Antolin
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, c/Julian Claveria, 33006 Oviedo, University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Puente-Moncada
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, c/Julian Claveria, 33006 Oviedo, University of Oviedo, Oviedo, Spain.
authors.forename: Santos
authors.initials: S
authors.lastname: Suarez
authors.affiliation: Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Gomez-Lobo
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, c/Julian Claveria, 33006 Oviedo, University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Rodriguez
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, c/Julian Claveria, 33006 Oviedo, University of Oviedo, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Oviedo, Spain.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Martin
mesh_terms: D000332:Aerobiosis; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D002813:Chondrosarcoma / Q000378:metabolism; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008550:Melatonin / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose; D008550:Melatonin