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J. Biol. Chem., Vol. 277, Issue 47, 45695-45703, November 22, 2002
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From the Department of Biochemistry, University of Illinois at
Urbana-Champaign, Urbana, Illinois 61801
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 µM
TAM and OHT and by 10-20 µM 17
Estrogen Receptor-dependent and Estrogen
Receptor-independent Pathways for Tamoxifen and
4-Hydroxytamoxifen-induced Programmed Cell Death*
-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 17-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.
*
This work was supported by NCI, National Institutes of
Health Grant CA90374.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 217-333-1788;
Fax: 217-244-5858; E-mail: djshapir@uiuc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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