Estrogen receptor blockade by the pure antiestrogen, ZM 182780, induces death of pituitary tumour cells.
Our previous studies have shown that even in the absence of estrogen, the estrogen receptor (ER) is still involved in growth by way of its conversion to a transcriptionally active state by growth inducing cytokines. The following paper now provides evidence that under more physiological conditions, the ER within the GH3 cell line used for the previous investigations, not only controls growth, but that transcriptional activity of the receptor is required for cell survival. Therefore when GH3 cells, maintained under serum and steroid replete conditions, are exposed to the pure antiestrogen ZM 182780 (10 nM), marked cell death is observed 72-120 h after first exposure. Studies on the nature of this cell death suggested that it had some of the reported characteristics of apoptosis or programmed cell death. Removal of steroids from the culture medium also resulted in cell death and this was enhanced by the addition of the pure antiestrogen. Both steroid withdrawal and ZM 182780 induced cell death was completely reversed by the inclusion of estrogens in the steroid free culture medium. In contrast, the non-steroidal antiestrogen, 4-hydroxytamoxifen (4-OHT) was not able to enhance steroid withdrawal death and at 1 microM, this compound was shown to have marked ER agonist activity. Further studies on the addition of conditioned medium from high density GH3 cell cultures, to low density steroid free cells, strongly suggested that the ER within these cells was responsible for the production of autocrine/paracrine survival factors.
Newton
C J
CJ
Max-Planck Institute of Psychiatry, Clinical Institute, Munich, Germany.
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003470:Culture Media / Q000737:chemistry; D017077:Culture Media, Conditioned; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004964:Estriol / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D004970:Estrone / Q000378:metabolism / Q000494:pharmacology; D000077267:Fulvestrant; D006915:Hydroxytestosterones / Q000494:pharmacology; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011388:Prolactin / Q000096:biosynthesis; D051381:Rats; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D013256:Steroids / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D003470:Culture Media; D017077:Culture Media, Conditioned; D004965:Estrogen Antagonists; D006915:Hydroxytestosterones; D011960:Receptors, Estrogen; D013256:Steroids; C032278:4,17 beta-dihydroxy-4-androstene-3-one; D000077267:Fulvestrant; D004970:Estrone; D004958:Estradiol; D011388:Prolactin; D008156:Luciferases; D004964:Estriol