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From the Department of Medicine/Endocrinology, Weill Medical College of Cornell University, New York, New York.
| Correspondence to: Dr Yuan-Shan Zhu, Department of Medicine/Endocrinology, Weill Medical College of Cornell University, 1300 York Ave, Box 149, New York, NY 10021 (e-mail: yuz2002{at}med.cornell.edu). |
| Received for publication December 28, 2004; accepted for publication February 10, 2005. |
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Abstract |
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-estradiol, but not by tamoxifen
via estrogen receptor (ER). In the presence of ERß,
17ß-estradiol and diethylstilbestrol had no significant effect, while
17-estradiol inhibited and ICI182780 and tamoxifen potentiated DHT
action. When both ER and ERß were present, all ER-ligands except
tamoxifen inhibited DHT action. The inhibition of DHT action by
17ß-estradiol via ER was mainly dependent on the DNA binding
domain, while the 17-estradiol effect was mainly dependent on the
ER carboxyl terminus. Treatment with DHT in LAPC-4 prostate tumor cells
that express a wild-type AR and both ERß and ER greatly increased
the PSA gene expression and cell growth. These DHT effects were significantly
attenuated by the addition of 17-estradiol, 17ß-estradiol, or
cyproterone acetate in a dose-dependent manner. These results indicate that
estrogens produce an ER-isoform– and ER-ligand–specific modulation
of DHT induction of PSA gene expression and prostate tumor cell growth,
providing a molecular basis for designing favorable agents for the prevention
and control of prostate cancer.
Key words: Androgen receptor, androgens, estrogen receptor
There are two natural potent androgens, testosterone and
dihydrotestosterone (DHT), in humans and mammals
(Zhu et al, 1998). Both
androgens interact with the androgen receptor (AR) to regulate androgen-target
gene expression. DHT, a potent androgen converted from testosterone by
5-reductase isozymes, is the major intracellular androgen and the major
mediator of androgen actions in the prostate
(Anderson and Liao, 1968;
Zhu et al, 2003). Clinical
studies indicate that 46XY subjects with an inherited DHT deficiency
attributable to a 5-reductase-2 gene defect have a small
undifferentiated prostate and an undetectable plasma prostate specific antigen
(PSA) level. DHT replacement therapy results in an enlargement of the prostate
and an elevation of plasma PSA levels in these subjects
(Mendonca et al, 1996;
Imperato-McGinley and Zhu,
2002; Zhu and Sung,
2005).
Like androgens, estrogens also display genomic actions via the estrogen
receptors (ERs). Both AR and ER are members of the nuclear receptor
superfamily and ligand-dependent nuclear transcription factors. Two ERs,
ER and ERß, have been identified in humans and animals. The ERs
share some common features but also possess differential estrogen actions
(Kuiper et al, 1997;
Paech et al, 1997). Both ERs
are expressed in prostate cells along with the AR
(Chang and Prins, 1999;
Lau et al, 2000). Growing
evidence indicates that estrogens can interact with androgens to modulate
androgen actions in the prostate. Estrogens have been shown to either inhibit
or potentiate androgen actions in the prostate, and theoretically they may
either inhibit or promote the development of prostate diseases
(Kumar et al, 1994; Suzuki et al, 1995;
vom Saal et al, 1997;
Bosland, 2000; Farrugia et al, 2000). The
mechanisms of these apparently opposing estrogen effects are unclear.
In the present report, we analyzed the interaction between DHT, a natural potent androgen, and estrogens in the regulation of PSA gene expression and prostate tumor cell growth. The results obtained indicate that estrogen analogs possess receptor-isoform and ligand-specific modulation of DHT-induced PSA gene transcription and prostate tumor cell growth, which may be mediated via differential mechanisms.
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Materials and Methods |
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mutants from Dr Chambon (IGBMC,
France), and PRL-null from Promega. Other plasmids used in the experiments,
ERE-tk-CAT, ER, thyroid hormone receptor 1
(TR1), vitamin D receptor, and RSV-ß-galactosidase (ß-gal),
have been described previously (Zhu et al,
1996).
Cell Culture and Cotransfection
CV-1 and DU-145 prostate tumor cells (ATCC, Rockville, Md) were grown in
Dulbecco modified Eagle medium (Sigma Chemical Co, St Louis, Mo), PC-3 cells
(ATCC) in RPMI-1640 medium supplemented with 10% fetal bovine serum (Gemini
Bio-Products Inc, Calabasas, Calif), 2 mM L-glutamine, 50 U/mL of
penicillin, and 50 µg/mL of streptomycin. All cells were maintained in a 5%
CO2, 95% air-humidified atmosphere at 37°C and were cultured in
phenol-red free medium with 5% stripped fetal bovine serum (Gemini
Bio-Products Inc) 24 hours before experiments.
CV-1 cell cotransfections were performed using the calcium phosphate precipitation method (ProFection, Promega), as previously described (Zhu et al, 1996). Briefly, CV-1 cells were plated on 60-mm dishes or 6-well plates with an approximately 60% density and were cotransfected with 4 µg of a CAT-base (PSA5.8-CAT, MMTV-CAT, or ERE-tk-CAT) reporter plasmid, 2 µg ß-gal, 1 µg receptor expression vector, and pBluescript-SK plasmid to a total of 15 µg DNA per 60-mm dish; or with 1.5 µg PSA5.8-pGL3 reporter plasmid, 1 µg PRL-null plasmid, 0.25 µg receptor expression vector, and pBluescript-SK plasmid to a total of 4 µg DNA per well, respectively. Sixteen hours later, the transfected cells were treated with various hormones for 48 hours, as indicated in the experiment. The CAT and luciferase activity was quantitated by phosphor-imager and Dual-Luciferase® Reporter Assay System (Promega), normalized to ß-gal activity and Renilla luciferase activity, respectively, presented as PSA transcription activity, and expressed as folds of vehicle control or as a percentage of DHT-treated level.
Cotransfection of DU-145 and PC-3 cells was carried out in 6-well plates using SuperFect Transfection kit from Qiagen (Valencia, Calif), following the manufacturer's instruction, and the luciferase activity was determined and presented as described above.
RNA Extraction and Reverse Transcription–Polymerase Chain Reaction Analysis of ER and ERß mRNA
Total cellular RNA was extracted by using TriPURE reagents (Roche
Diagnostic Inc, Indianapolis, Ind), and the concentrations of RNA were
determined by ultraviolet absorbance at 260 nm.
Reverse transcription–polymerase chain reaction (RT-PCR) was carried
out using the Titan 1-tube RT-PCR system (Roche Diagnostic) with 1 µg of
total cellular RNA (Zhu et al,
2003). A pair of specific primers, 5'-ATGAGAGCTGCC
AACCTTTG-3' and 5'-AGAAATGTGTACACTCCAGAAT-3', from human
ER gene, and a pair of primers, 5'-GATGAGGGGAAATGCGTAGA-3'
and 5'-CTTGTTACTCGCATGCCTGA-3', from human ERß gene,
respectively, were used. The RT-PCR conditions were 50°C for 30 minutes,
following 94°C for 2 minutes, and then 40 cycles of 94°C for 30
seconds, 62°C for 30 seconds for ER, or 60°C for 30 for
ERß, and 68°C for 45 seconds, following a final cycle of 68°C for
7 minutes. The PCR products were fractionated in a 2% agarose gel and
visualized by ethidium bromide staining. The expected sizes of specific PCR
products for ER and ERß are 530 and 321 bp, respectively. Total
cellular RNA from human ovary was used as a positive control, and yeast tRNA
was used as a negative control of RT-PCR.
The Determination of Viable Cell Number
For analysis of cell growth, LAPC-4 prostate tumor cells (a gift from Dr C.
Sawyer, University of California, Los Angeles) were cultured in Isove modified
Eagle medium (IMEM) supplemented with 15% fetal bovine serum, 2 mM
L-glutamine, 1 nM R1881, 50 U/mL of penicillin, and 50 µg/mL of
streptomycin. R1881 was withdrawn 48 hours before cell passage for
experiments. LAPC-4 cells were plated in 96-well plates (2.5 x
104 cells/well) in phenol-red free IMEM with 5% stripped fetal
bovine serum, and 24 hours later, they were treated with various hormones for
72 hours, as indicated in the experiment. The number of viable cells was
determined using the CellTiter One Solution Cell Proliferation Assay kit from
Promega and was presented as a percentage of vehicle control in the same
experiment.
PSA Determination
The levels of total PSA in the culture medium were determined using an
enzyme-linked immunosorbent assay kit from Diagnostic Systems Laboratories Inc
(Wester, Tex) following the manufacturer's instruction.
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Statistics
The data are presented as mean plus standard error of the mean (SEM).
One-way analysis of variance (ANOVA) following Student Newman-Keuls test was
used to analyze the dose-response effects and to determine the difference
among multiple groups. A P value of less than .05 was accepted as the
level of statistical significance.
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Results |
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Cotransfection of AR with ER or ERß in CV-1 cells noticeably,
but not significantly, decreased the DHT-induced PSA transcription activity
(Figure 2a). Concomitant
treatment of the cotransfected cells with E2 (10 nM) greatly attenuated the
DHT-induced PSA transcription activity via ER, regardless of induction
by either a low (0.5 nM) or a high dose (10 nM) of DHT
(Figure 2b). However, in the
presence of ERß (Figure
2c), E2 had no significant effect, even at high doses (up to 1
µM) of E2, or with high levels (up to 4 µg) of ERß cotransfection.
The levels of ERß cotransfected were detectable by Western blot analysis
and were functionally sufficient to mediate E2 induction of estrogen-target
gene expression using a consensus ERE-directed CAT reporter gene
(ERE-tk-CAT) in the same system (data not shown).
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was not affected by the
addition of ICI182780 (ICI), a pure estrogen antagonist
(Figure 2d). Interestingly,
ICI, like E2, also inhibited DHT-induced PSA transcription activity via
ER, as shown in Figure
2d. However, the combination of E2 (10 nM) and ICI (100 nM) did
not display additive or synergistic effects at the doses tested.
The inhibition of DHT action by E2 via ER was an ER and
estrogen-specific event, since cotransfection of AR with either TR1 or
vitamin D receptor, treated with corresponding ligand triiodothyronine or
1,25-dihydro-xyvitamin D, either had no significant effect or slightly
potentiated DHT action at high-dose (1 µM) hormone treatment (data not
shown).
A similar ER-isoform–specific inhibition of DHT (10 nM)–induced androgen-target gene transcription by E2 (10 nM) was observed by cotransfection of a MMTV-CAT reporter construct in CV-1 cells (data not shown), which has a CAT-reporter gene directed by the mouse mammary tumor virus (MMTV) promoter that contains a consensus androgen response element (Yeh et al, 1998).
2. ER-Ligand– and ER-Isoform–Specific Modulation of DHT-Induced PSA Transcription Activity in CV-1 Cell Cotransfection
By using DHT induction of PSA transcription activity in CV-1 cell
cotransfection as a model system, the effects of various ER-ligands on the
modulation of DHT action via ER or ERß were examined. As shown in
Figure 3a and b, similar to E2,
diethylstilbestrol, a synthetic potent estrogen agonist, inhibited DHT-induced
PSA transcription activity via ER in a dose-dependent manner, while it
had no significant effect in the presence of ERß. In contrast, tamoxifen,
a partial estrogen agonist or a selective ER modulator, did not affect
DHT-induced PSA transcription activity via ER, while it significantly
potentiated DHT action via ERß. ICI, a pure estrogen antagonist,
inhibited DHT action via ER, while it might stimulate it via ERß
at a high concentration (1 µM).
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Interestingly, 17-estradiol (E2), an isomer of E2 and a
weaker estrogen agonist, produced a dose-dependent inhibition of DHT action
via either ER or ERß (Figure 3a
and b). The effects of all ER-ligands were dependent on ER, since
they did not significantly alter DHT action in the absence of ER
cotransfection.
When AR, ER, and ERß were cotransfected at a 1:1:1 ratio, as
shown in Figure 3c, treatment
with E2, E2, or diethylstilbestrol inhibited DHT action; tamoxifen
potentiated DHT action; and ICI inhibited DHT action at a dose of 10 nM, while
it had no significant effect at 100 nM.
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E2 inhibited DHT action via
ER, while tamoxifen had no significant effect
(Figure 4a). In the presence of
ERß, E2 had no significant effect, while E2 significantly
inhibited and tamoxifen potentiated DHT action
(Figure 4b).
In PC-3 cells (Figure 4c and
d), both E2 and E2 significantly inhibited DHT action,
while tamoxifen had no effect via ER at a dose of 100 nM. In the
presence of ERß, tamoxifen potentiated DHT action, but E2 and E2
failed to effect DHT action at the doses tested.
4. The Inhibition of DHT Action by E2 and E2 Via ER Involved Different Receptor Domains
To analyze the functional significance of each ER domain in this
androgen-estrogen interaction, various ER mutants, as illustrated in
Figure 5a
(Kumar et al, 1987), were
studied by cotransfection in CV-1 cells. A deletion of ER DNA binding
domain (DBD, HE11) completely blocked the E2 inhibition of DHT action, while
it only partially interfered with E2 action
(Figure 5b). A deletion of the
carboxyl-terminal domain (F domain, HE13) completely blocked the E2
inhibition of DHT action but only partially affected E2 action
(Figure 5c). Deletion of
ER amino-terminal domain (HE19) had no significant effects on either E2
or E2 inhibition of DHT action
(Figure 5d) although this
mutant greatly affects the E2-induced estrogen-target gene expression
(Kumar et al, 1987). Both E2
and E2 failed to inhibit DHT action in the presence of ERd-DBD alone
(HE20, Figure 5e).
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Level Was Quite Low expression was quite low or undetectable,
as shown in Figure 6.
Additionally, in MDA Pca-2b cells, an androgen-independent prostate cancer
cell line (Zhao et al, 2000), both ERs were detected, but ERß was predominant. As expected, both ERs
were expressed in human ovarian tissues.
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E2, or cyproterone acetate (an AR antagonist) in a
dose-dependent manner.
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E2 on DHT induction of LAPC-4 cell
growth were examined. Treatment of LAPC-4 cells with DHT for 72 hours produced
a dose-dependent induction of cell growth, as shown in
Figure 7b. This DHT-induced
LAPC-4 cell growth was significantly inhibited by the addition of E2,
E2, or cyproterone acetate in a dose-dependent manner
(Figure 7c). However, treatment
with E2 or E2 alone for 72 hours had no significant effects on LAPC-4
cell growth.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Using DHT-induced PSA transcription in cotransfection assays as a model
system, the effects of ER-isoforms and various ER-ligands on modulation of
androgen action were analyzed. The observation that E2 inhibited DHT-induced
PSA transcription activity and MMTV-CAT activity via ER is in agreement
with the results of previous studies
(Kumar et al, 1994;
Panet-Raymond et al, 2000). More importantly, we demonstrate the ER-isoform and ER-ligand specificity in
this androgen-estrogen interaction. Based on these results, ER-ligands are
classified into 4 different categories related to their effects on androgen
action (the Table). This
classification is different from the pharmacological classification based on
estrogenic activity. E2, E2, and ICI all inhibit DHT action via
ER, although they are pharmacologically classified as an estrogen
agonist, a weaker agonist, and a pure antagonist, respectively.
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The observed ER-isoform–specific actions are consistent with the
demonstration that ER and ERß possess distinctive action in the
regulation of gene expression. Paech et al
(1997) have shown that
ER and ERß signal in opposite ways in the presence of E2 from an
AP1 site; with ER, E2 activates transcription, whereas with ERß,
E2 inhibits transcription. Panet-Raymond et al
(2000) observed that E2
inhibits androgen action via ER, but not via ERß, a result that is
in agreement with our current results. Taken together, these data indicate
that ER and ERß possess differential actions in mediating
ligand-specific activity, although they share high homology and common
functional modalities.
An ER-ligand–specific modulation of DHT action is observed via either
ER or ERß. This ligand specificity is consistent with the concept
that different ER-ligands cause differential conformational changes in the ERs
(Egner et al, 2001; Nilsson et al, 2001;
Margeat et al, 2003). The
differential changes in ER conformation by various ligands may result in a
recruitment of various transcriptional factors or coregulators
(Shang and Brown, 2002;
Margeat et al, 2003) and may
process different downstream actions. This explains the differential ER-ligand
effects, but it does not explain why various ER-ligands, including agonist,
partial agonist, and pure antagonist, all lead to the inhibition of DHT action
via ER. The observation that both E2 and ICI inhibit DHT action is
consistent with previous demonstrations that both E2 and ICI induce the same
target gene transcription (Kim et al,
2003) and cause proteasome-dependent ER degradation
(Preisler-Mashek et al,
2002).
A stereo-specificity of E2 and E2 in modulating DHT action is
observed. Like E2, E2 binds to ERs and processes estrogenic activity,
although in a much weaker fashion (Edwards
and McGuire, 1980). Unlike E2, which inhibits DHT-induced PSA
transcription via ER only in cotransfection assays, E2 inhibits
DHT action via either ER or ERß.
The importance of ER functional domains in this estrogen-androgen
interaction is analyzed using ER mutants. The E2-inhibition of DHT
action via ER mainly involves the DBD. However, gel shift analysis
shows that neither ER nor ERß directly binds to any of the 3
functional AREs in the human PSA promoter (our unpublished data), indicating
that direct competition of ARE-binding between ligand-AR and ligand-ER is
unlikely. On the other hand, E2 inhibition of DHT action via ER
is completely eliminated when the ER F-domain is deleted. The F-domain
is highly variable in the nuclear receptor superfamily, and there is little
homology between ER and ERß. The ER F-domain potentially
contains helix-13 and ß-strand motifs
(Kumar et al, 1987;
Kim et al, 2003). The
functional significance of the ER F-domain is just emerging. It is
required for the agonist/antagonist action of tamoxifen
(Schwartz et al, 2002) and the
E2 activation of ER/SP1 pathway
(Kim et al, 2003).
The biological significance of this androgen-estrogen interaction is
exemplified by determining the effects of E2 and E2 on the regulation
of DHT induction of PSA gene expression and cell growth in LAPC-4 prostate
tumor cells. Previous studies show that LAPC-4 cells express a wild-type AR
and are sensitive to androgen stimulation
(Klein et al, 1997). We here
demonstrate that LAPC-4 cells also express ERs with predominantly ERß and
low level of ER, which is consistent with previous demonstration in
other prostate tumor cells (Lau et al,
2000). As expected, treatment with DHT in LAPC-4 cells increases
PSA expression and cell growth (see Figure
7). These DHT effects are significantly inhibited by
coad-ministration of E2, or E2 in a dose-dependent manner. The
inhibitory effects of these estrogen analogs are as potent as cyproterone
acetate, an AR antagonist, although they act via different mechanisms.
The estrogen inhibition of DHT-induced PSA gene expression and cell growth
in LAPC-4 cells may be mediated via ERs, as both ER and ERß are
expressed in these cells. If this is the case, then the data obtained in
LAPC-4 cells are consistent with the cotransfection studies, in which both E2
and E2 inhibit DHT-induced PSA transcription activity when both
ER and ERß are cotransfected in the cells. This hypothesis is
further supported by our recent studies showing that the estrogen inhibition
of AR action is mainly mediated via ERß using RNA interference analysis
(unpublished data). However, it should be noted that the
receptor-isoform– and ligand-specific modulation of DHT action by
estrogens needs to be further evaluated in prostate cells, and there is no
direct linkage between DHT-induced PSA gene expression and prostate tumor cell
growth. This notion is supported by comparing the dose-response data between
estrogen inhibition of DHT-induced PSA expression and estrogen inhibition of
DHT-induced cell growth in LAPC-4 cells (see
Figure 7a and c), in which
differential dose-response curves are observed. Although PSA has been shown to
degrade insulin-like growth factor binding protein 3, thereby leading to a
potentiation of insulin-like growth factor action on cell growth by in vitro
analysis (Cohen et al, 1994),
such PSA action has not been demonstrated in vivo, and the significance of PSA
in prostate pathogenesis remains to be determined.
In vivo studies have shown that estrogens can either inhibit or enhance androgen effects, although the mechanisms of these apparent opposing estrogen actions are not explored. The present analyses using in vitro cotransfection assays provide a reasonable, potential explanation of these seemingly opposing estrogen actions. Since the outcome of androgen-estrogen interaction is cell-type, ER-isoform– and ligand-specific, the final result can be either inhibitory or stimulatory depending on the ER-isoforms expressed in the cells, as well as the ligands used in the experiment. Further study using ER knockout animals will provide valuable information for androgen-estrogen interaction in the prostate.
In summary, estrogens have been used in hormonal therapy of prostate cancer, presumably by inhibiting testosterone biosynthesis via the negative feedback of the hypothalamus-pituitary-gonadal axis (Huggins and Hodges, 1941). Our current study provides an additional mechanism for estrogens acting directly through ERs to antagonize androgen actions within the cells. The demonstration of ER-isoform and ligand specificity mediated via differential mechanisms in androgen-estrogen interaction explains the seemingly opposing estrogen action in the prostate and provides important information for the development of new estrogen analogs in the prevention and control of prostate cancer.
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Acknowledgments |
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and ER mutant expression
vectors; to Dr Liao (The Ben May Institute, Chicago, Ill) for the AR
expression vector; to Dr Sawyer (UCLA) for LAPC-4 cells; to Dr Wakeling
(Zeneca Pharmaceuticals, United Kingdom) for ICI182780; and to Dr C. Chang
(University of Rochester, NY) for valuable discussion. |
Footnotes |
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