title: Melatonin blocks the activation of estrogen receptor for DNA binding.
abstract: The present study shows that melatonin prevents, within the first cell cycle, the estradiol-induced growth of synchronized MCF7 breast cancer cells. By using nuclear extracts of these cells, we first examined the binding of estradiol-estrogen receptor complexes to estrogen-responsive elements and found that the addition of estradiol to whole cells activates the binding of the estrogen receptor to DNA whereas melatonin blocks this interaction. By contrast, melatonin neither affects the binding of estradiol to its receptor nor the receptor nuclear localization. Moreover, we also show that addition of estradiol to nuclear extracts stimulates the binding of estrogen receptor to DNA, but this activation is also prevented by melatonin. The inhibitory effect caused by melatonin is saturable at nanomolar concentrations and does not appear to be mediated by RZR nuclear receptors. The effect is also specific, since indol derivatives do not cause significant inhibition. Furthermore, we provide evidence that melatonin does not interact with the estrogen receptor in the absence of estradiol. Together, these results demonstrate that melatonin interferes with the activation of estrogen receptor by estradiol. The effect of melatonin suggests the presence of a receptor that, upon melatonin addition, destabilizes the binding of the estradiol-estrogen receptor complex to the estrogen responsive element.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, 33006 Oviedo, Spain.
authors.forename: A G
authors.initials: AG
authors.lastname: Rato
authors.forename: J G
authors.initials: JG
authors.lastname: Pedrero
authors.forename: M A
authors.initials: MA
authors.lastname: Martinez
authors.forename: B
authors.initials: B
authors.lastname: del Rio
authors.forename: P S
authors.initials: PS
authors.lastname: Lazo
authors.forename: S
authors.initials: S
authors.lastname: Ramos
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001693:Biological Transport, Active / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism*; D044094:Receptors, Melatonin; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D004273:DNA, Neoplasm; D004965:Estrogen Antagonists; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D044094:Receptors, Melatonin; D011994:Recombinant Proteins; D013629:Tamoxifen; D004958:Estradiol; D008550:Melatonin