title: Estrogens stimulate tamoxifen-induced neuronal cell apoptosis in vitro: a possible nongenomic action.
abstract: Estrogens are implicated in the regulation of neuronal cell death and survival in the nervous system. However, the molecular mechanisms are largely unknown. Here, we investigated effects of estrogens and an anti-estrogen compound, tamoxifen (TMX), on the death/survival of GT1-7 hypothalamic neuronal cells. Endogenous nuclear estrogen receptors (ERs) in these cells were found to be inactive on the basis of luciferase assay. Treatment of cells with TMX stimulated cell death, which was associated with DNA ladder formation characteristic of apoptosis. Both 17-beta estradiol, which stimulates ER-mediated transcription, and 17-alpha estradiol, which does not, had little effect on cell survival. Both estradiols, however, significantly potentiated TMX-induced cell death. Similar effects were obtained by estriol, but more remarkable effects were observed by quinestrol, an ethinyl estradiol derivative, which has an ether-modification at the C3 position. Furthermore, either TPA or forskolin, a potent stimulator of protein kinase C or A, respectively, also stimulated TMX-induced cell death. Taken together, these results may suggest that genomic activity through ERs is not prerequisite for estrogen stimulation of TMX-induced apoptosis, but that the cell death pathway of TMX could be modulated at the cytoplasmic level by estrogens, whose activity is dependent upon their molecular structure.
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla 92093-0624, USA. mhashimoto@ucsd.edu
authors.forename: M
authors.initials: M
authors.lastname: Hashimoto
authors.forename: S
authors.initials: S
authors.lastname: Inoue
authors.forename: M
authors.initials: M
authors.lastname: Muramatsu
authors.forename: E
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D053938:DNA Fragmentation; D004958:Estradiol / Q000494:pharmacology; D004964:Estriol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D004997:Ethinyl Estradiol / Q000494:pharmacology; D007031:Hypothalamus; D007700:Kinetics; D008156:Luciferases / Q000096:biosynthesis; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D016133:Polymerase Chain Reaction; D011800:Quinestrol / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013629:Tamoxifen / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D014981:Xenopus
chemical_list: D004967:Estrogens; D009414:Nerve Growth Factors; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D013629:Tamoxifen; D005576:Colforsin; D004997:Ethinyl Estradiol; D004958:Estradiol; D008156:Luciferases; D004964:Estriol; D011800:Quinestrol; D013755:Tetradecanoylphorbol Acetate