title: Fas/Fas ligand regulation mediates cell death in human Ewing's sarcoma cells treated with melatonin.
abstract: BACKGROUND
  Despite recent advances in cancer therapy, the 5-year survival rate for Ewing's sarcoma is still very low, and new therapeutic approaches are necessary. It was found previously that melatonin induces cell death in the Ewing's sarcoma cell line, SK-N-MC, by activating the extrinsic apoptotic pathway.
  
  
  METHODS
  Melatonin actions were analysed by metabolic viability/survival cell assays, flow cytometry, quantitative PCR for mRNA expression, western blot for protein activation/expression and electrophoretic mobility shift assay for transcription factor activation.
  
  
  RESULTS
  Melatonin increases the expression of Fas and its ligand Fas L, this increase being responsible for cell death induced by the indolamine. Melatonin also produces a transient increase in intracellular oxidants and activation of the redox-regulated transcription factor Nuclear factor-kappaB. Inhibition of such activation prevents cell death and Fas/Fas L upregulation. Cytotoxic effect and Fas/Fas L regulation occur in all Ewing's cell lines studied, and do not occur in the other tumour cell lines studied where melatonin does not induce cell death.
  
  
  CONCLUSIONS
  Our data offers new insights in the study of alternative therapeutic strategies in the treatment of Ewing's sarcoma. Further attention deserves to be given to the differences in the cellular biology of sensitive tumours that could explain the cytotoxic effect of melatonin and the increase in the level of free radicals caused by this molecule, in particular cancer types.
authors.affiliation: Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, C/ Julian Claveria 6, 33006 Oviedo, Spain.
authors.forename: G
authors.initials: G
authors.lastname: García-Santos
authors.forename: V
authors.initials: V
authors.lastname: Martin
authors.forename: J
authors.initials: J
authors.lastname: Rodríguez-Blanco
authors.forename: F
authors.initials: F
authors.lastname: Herrera
authors.forename: S
authors.initials: S
authors.lastname: Casado-Zapico
authors.forename: A M
authors.initials: AM
authors.lastname: Sánchez-Sánchez
authors.forename: I
authors.initials: I
authors.lastname: Antolín
authors.forename: C
authors.initials: C
authors.lastname: Rodríguez
mesh_terms: D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008550:Melatonin / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species; D012512:Sarcoma, Ewing / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D007211:Indoles; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D019014:fas Receptor; C067042:indolamine; D008550:Melatonin