Delayed and persistent ERK1/2 activation is required for 4-hydroxytamoxifen-induced cell death.
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.
Zhou
Jian-Hua
JH
Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA.
Yu
David V
DV
Cheng
Jingwei
J
Shapiro
David J
DJ
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
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
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14783-8
12415108
Trends Endocrinol Metab. 2002 Dec;13(10):422-7
12431838
J Biol Chem. 2002 Nov 22;277(47):45695-703
12244117
J Biol Chem. 2003 Jan 24;278(4):2701-12
12421825
Science. 2003 Mar 21;299(5614):1859-63
12649474
Endocr Relat Cancer. 2003 Jun;10(2):331-45
12790794
J Biol Chem. 2003 Oct 17;278(42):41355-66
12904306
Endocr Rev. 2004 Feb;25(1):45-71
14769827
Trends Endocrinol Metab. 2001 May-Jun;12(4):152-6
11295570
Endocrinology. 2001 Jun;142(6):2200-4
11356663
J Biol Chem. 2001 Aug 3;276(31):29588-95
11395491
Apoptosis. 2001 Dec;6(6):469-77
11595837
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13681-6
11717429
Mol Endocrinol. 2002 Jan;16(1):70-84
11773440
Mol Endocrinol. 2002 Jan;16(1):100-15
11773442
J Biol Chem. 2002 Feb 8;277(6):4010-7
11726647
J Steroid Biochem Mol Biol. 2002 Feb;80(2):239-56
11897507
Science. 2002 Mar 29;295(5564):2465-8
11923541
Oncogene. 2002 Jun 6;21(25):4000-8
12037682
Mol Cell Endocrinol. 2005 Jun 15;237(1-2):11-23
15925090
J Cell Physiol. 2005 Aug;204(2):678-86
15744749
Endocrinology. 2005 Jan;146(1):56-63
15514082
Cancer Res. 2004 Dec 15;64(24):9115-23
15604281
Endocrinology. 2005 Feb;146(2):624-32
15539556
Mol Cell Neurosci. 2005 Mar;28(3):452-61
15737736
Mol Endocrinol. 2000 Oct;14(10):1649-60
11043579
Mol Cell Biol. 2000 Dec;20(23):8720-30
11073973
Cell. 2001 Mar 9;104(5):719-30
11257226
Endocr Rev. 2001 Apr;22(2):153-83
11294822
Eur J Neurosci. 2005 May;21(9):2311-9
15932590
Free Radic Biol Med. 2005 Aug 1;39(3):345-54
15993333
Mol Endocrinol. 2005 Aug;19(8):1951-9
15705661
Eur J Cancer. 2005 Sep;41(13):1980-9
15964182
Toxicol Appl Pharmacol. 2005 Oct 1;208(1):46-56
15901486
Cancer Lett. 2005 Dec 8;230(1):1-5
16253755
Endocrinology. 2005 Dec;146(12):5388-96
16123166
Endocrinology. 2005 Dec;146(12):5397-406
16123167
Mol Cells. 2005 Feb 28;19(1):60-6
15750341
Science. 2005 Mar 11;307(5715):1625-30
15705806
Exp Cell Res. 2005 Apr 15;305(1):23-32
15777784
Maturitas. 2005 Apr 11;50(4):247-58
15780523
Clin Cancer Res. 2005 Mar 15;11(6):2345-54
15788686
Life Sci. 2005 Apr 29;76(24):2817-25
15808882
J Steroid Biochem Mol Biol. 2005 Feb;93(2-5):319-23
15860276
Int J Oncol. 2005 Jun;26(6):1575-80
15870872
Neuroscience. 2005;133(1):343-52
15893655
Neurochem Res. 2005 Feb;30(2):263-70
15895830
Endocr Rev. 2005 May;26(3):393-9
15814849
Apoptosis. 2005 May;10(3):597-609
15909121
Trends Pharmacol Sci. 1999 Oct;20(10):408-12
10577253
J Biol Chem. 2000 Jan 7;275(1):479-86
10617642
J Biol Chem. 2000 Feb 11;275(6):4475-83
10660621
Mol Cell Biol. 2000 Apr;20(8):2890-901
10733592
J Mammary Gland Biol Neoplasia. 2000 Jan;5(1):107-15
10791773
Clin Cancer Res. 2000 May;6(5):2028-36
10815929
Genes Cells. 2000 Aug;5(8):593-601
10947845
J Natl Cancer Inst Monogr. 2000;(27):135-45
10963625
Mol Biol Cell. 2000 Sep;11(9):2915-32
10982390
Nature. 2000 Sep 28;407(6803):538-41
11029009
Cancer Res. 2000 Oct 1;60(19):5395-400
11034078
Mol Cell Endocrinol. 2002 Jun 28;192(1-2):93-104
12088871
Mol Endocrinol. 2002 Aug;16(8):1778-92
12145334
Cancer Lett. 2002 Nov 28;185(2):131-8
12169386
Cancer Res. 2004 Feb 15;64(4):1522-33
14973112
Mol Endocrinol. 2004 May;18(5):1096-108
14963108
Steroids. 2004 Aug;69(8-9):523-9
15288764
Mol Endocrinol. 1990 Oct;4(10):1465-73
2178215
Proc Natl Acad Sci U S A. 1992 May 15;89(10):4658-62
1584801
Cell. 1995 Jan 27;80(2):179-85
7834738
J Biol Chem. 1995 Nov 17;270(46):27489-94
7499206
Science. 1995 Dec 1;270(5241):1491-4
7491495
EMBO J. 1996 May 1;15(9):2174-83
8641283
Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12626-30
8901633
Biochem Biophys Res Commun. 1997 Jun 9;235(1):99-102
9196043
Crit Rev Eukaryot Gene Expr. 1998;8(2):125-40
9714894
Blood. 1998 Sep 1;92(5):1749-57
9716605
Science. 1998 Aug 28;281(5381):1312-6
9721091
Oncology. 1998 Dec;55 Suppl 1:5-10
9852396
Cell. 1998 Dec 23;95(7):927-37
9875847
J Clin Invest. 1999 Feb;103(3):401-6
9927501
J Neurosci. 1999 Apr 1;19(7):2455-63
10087060
Mol Endocrinol. 1999 Apr;13(4):632-43
10194768
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4686-91
10200323
Curr Opin Cell Biol. 1999 Apr;11(2):184-9
10209149
Mol Endocrinol. 2002 Oct;16(10):2202-14
12351686