title: Delayed and persistent ERK1/2 activation is required for 4-hydroxytamoxifen-induced cell death.
abstract: Tamoxifen (Tam), and its active metabolite, 4-hydroxytamoxifen (OHT), compete with estrogens for binding to the estrogen receptor (ER). Tam and OHT can also induce ER-dependent apoptosis of cancer cells. 10-100nM OHT induces ER-dependent apoptosis in approximately 3 days. Using HeLaER6 cells, we examined the role of OHT activation of signal transduction pathways in OHT-ER-mediated apoptosis. OHT-ER activated the p38, JNK and ERK1/2 pathways. Inhibition of p38 activation with SB203580, or RNAi-knockdown of p38alpha, moderately reduced OHT-ER mediated cell death. A JNK inhibitor partly reduced cell death. Surprisingly, the MEK1/2 inhibitor, PD98059, completely blocked OHT-ER induced apoptosis. EGF, an ERK1/2 activator, enhanced OHT-induced apoptosis. OHT induced a delayed and persistent phosphorylation of ERK1/2 that persisted for >80h. Addition of PD98059 as late as 24h after OHT largely blocked OHT-ER mediated apoptosis. The antagonist, ICI 182,780, blocked both the long-term OHT-mediated phosphorylation of ERK1/2 and OHT-induced apoptosis. Our data suggests that the p38 and JNK pathways, which often play a central role in apoptosis, have only a limited role in OHT-ER-mediated cell death. Although rapid activation of the ERK1/2 pathway is often associated with cell growth, persistent activation of the ERK1/2 pathway is essential for OHT-ER induced cell death.
authors: Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA.
authors: Jian-Hua
authors: JH
authors: Zhou
authors: David V
authors: DV
authors: Yu
authors: Jingwei
authors: J
authors: Cheng
authors: David J
authors: DJ
authors: Shapiro
mesh_terms: D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D000077267:Fulvestrant; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D004965:Estrogen Antagonists; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011960:Receptors, Estrogen; D013629:Tamoxifen; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol; D004815:Epidermal Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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