title: Estrogen receptor-dependent and estrogen receptor-independent pathways for tamoxifen and 4-hydroxytamoxifen-induced programmed cell death.
abstract: The therapeutic efficacy of tamoxifen (TAM) in cancer therapy is thought to arise primarily from its ability to compete with estrogens for binding to the estrogen receptor (ER). We show that TAM and its active metabolite, 4-hydroxytamoxifen (OHT), can actively induce programmed cell death through distinct ER-dependent and ER-independent pathways. The ER-independent pathway is activated by 10-20 microm TAM and OHT and by 10-20 microm 17beta-estradiol and raloxifene, and occurs in ER-negative cells. The ER dependence of a second pathway, caused by submicromolar concentrations of TAM and OHT, was demonstrated by the ability of the ER ligands 17beta-estradiol, raloxifene, and ICI 182,780 to effectively block the cell death-inducing effects of TAM and OHT. Because the p38-specific inhibitor SB203580 blocks OHT.ER-induced cell death, stress kinase pathways are likely involved. ER-independent cell death triggers classic caspase-dependent apoptosis. However, although OHT.ER triggers some hallmarks of apoptosis, including Bax translocation and cytochrome c release, the absence of poly(ADP-ribose) polymerase cleavage or DNA laddering indicates that the death pathway involved is caspase-independent. The OHT.ER-dependent cell death pathway appears to diverge from classical apoptosis at the level of caspase 9 activation. The ability to promote ER-dependent programmed cell death represents a novel activity of TAM and OHT.
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Obrero
authors.forename: David V
authors.initials: DV
authors.lastname: Yu
authors.forename: David J
authors.initials: DJ
authors.lastname: Shapiro
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002458:Cell Fractionation; D048429:Cell Size; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D000077267:Fulvestrant; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D008854:Microscopy, Electron; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D004965:Estrogen Antagonists; D011506:Proteins; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D000077267:Fulvestrant; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D005047:Etoposide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases