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From the Medical Research Council Group in Molecular Endocrinology, CHUL Research Center, Laval University, Quebec, 61V 462, Canada
Address all correspondence and requests for reprints to: Alain Bélanger, Laboratory of Molecular Endocrinology CHUL Research Center, 2705 Laurier Boulevard, Québec, G1V 4G2, Canada. E-mail: Alain.Belanger{at}crchul.ulaval.ca
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-reductase to DHT, whereas testosterone secreted from the testis is
also converted to DHT. In recent years, enzymes that catalyze the
production of DHT in steroid target tissues have been well investigated
(4, 5, 6); however, enzymes that are involved in the catabolism and
elimination of steroids in these tissues, including uridine
diphospho-glucuronosyltransferase (UGT) enzymes, have received much
less attention.
UGT enzymes catalyze the transfer of the glucuronyl group from uridine
5'-diphosphoglucuronic acid (UDPGA) to active endogenous and exogenous
molecules having functional groups of oxygen, nitrogen, sulfur, and
carbon. The resulting glucuronide products are more polar, generally
water soluble, less toxic, and more easily excreted than the substrate
molecule. Examples of endogenous substrates that are glucuronidated
include bilirubin, bile acids, and steroids, whereas xenobiotics such
as drugs and pollutants are also detoxified by UGT enzymes (7, 8).
Glucuronidation of a steroid molecule also prevents its interaction
with its nuclear receptor and favors elimination of the polar steroid
from the tissue. Therefore, the glucuronidation process is potentially
an important pathway of steroid metabolism. Considering the high levels
of glucuronidated DHT metabolites such as androsterone (ADT) and
androstane-3,17ß-diol (3-DIOL) and the presence of UGT enzymes
found in several human extrahepatic tissues including the prostate
(9, 10, 11, 12, 13), we have recently proposed that glucuronidation may be involved
in regulating the androgen levels in these tissues. In fact, the
concept of detoxification by glucuronidation in the liver could be
extended to the extrahepatic tissues where endogenous compounds such as
steroids could be glucuronidated for elimination.
The human prostate expresses UGT2B15 and UGT2B17, which have been
demonstrated to glucuronidate androgens (11, 12, 13, 14). Similarly to other
UGT enzymes, UGT2B15 can conjugate several classes of compounds (12, 14), however, it is also specific for DHT and 3-DIOL that are
glucuronidated at the 17ß-OH position. UGT2B17 is also specific for
DHT and 3-DIOL, but it can also conjugate ADT at the 3-OH
position (13). Interestingly, ADT-G that is conjugated by UGT2B17 is
the predominant steroid glucuronide in the plasma and in the prostate
of humans (9, 10).
Although androgens are important regulators in the prostate, several findings indicate that the prostate also produces peptide growth factors capable of enhancing or inhibiting cellular proliferation of the prostate and modify its function (15, 16, 17). In steroid-dependent prostatic tumors, androgens have been shown to modulate the local production of growth factors that in turn have been demonstrated to regulate tumor cell proliferation (18, 19, 20, 21, 22, 23). In addition to modulating steroidogenesis in Leydig cells, ovarian granulosa cells, and adrenal cells, growth factors influence the activity of steroid transforming enzymes in steroid target tissues such as the prostate, skin, and breast (24, 25, 26, 27, 28, 29).
The purpose of the present study was to investigate the regulation of
expression of UGT2B15 and UGT2B17 in human prostate LNCaP cells by DHT
and EGF. We have recently demonstrated that LNCaP cells, which are used
extensively as a model of human prostate epithelial cells, are capable
of converting 5-reduced C19 steroids into glucuronide
conjugates and of expressing UGT transcripts such as UGT2B15 and
UGT2B17 (13, 30, 31, 32). It has been shown that the steady-state levels of
UGT2B transcripts are repressed by androgens accompanied by a decrease
of DHT and ADT glucuronidation in LNCaP cells (32). In this report, we
demonstrate that the level of different steroid conjugating UGT2B
transcripts are differentially regulated in human prostate LNCaP cells.
We show that DHT and EGF can decrease the level of UGT2B17 transcript
and protein, whereas the level of UGT2B15 messenger RNA (mRNA) remain
unchanged. The decrease in the level of UGT2B17 was also manifested by
a decreased production of glucuronidated DHT in LNCaP cells. In
addition, it was also found that the UGT2B17 protein is more labile
than UGT2B15, indicating that regulation of UGT2B17 expression can lead
to a more rapid change in the level of glucuronidated steroids. These
results demonstrate that UGT2B17 is a major enzyme catalyzing the
glucuronidation of androgens in human prostate LNCaP cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-[32P]-dUTP (3000 Ci/mmol) were
purchased from Amersham (Oakville, Canada). Unlabeled DHT and ADT were
obtained from Steraloids Inc. (Wilton, NH). Protein assay reagents were
from Bio-Rad (Richmond, CA) and monoclonal anti-EGF-R antibody (Ab-1)
was purchased from Calbiochem (Cambridge, MA). Restriction enzymes and
other molecular biology reagents were from Pharmacia LKB Biotechnology
Inc. (Milwaukee, WI), Life Technologies (Burlington, Canada),
Stratagene (La Jolla, CA) and Boehringer Mannheim (Indianapolis,
IN).
Cell culture
The LNCaP cell line was obtained from American Type Culture
Collection (Rockville, MD) at passage 21 and used between passages 22
to 29. The cells were routinely maintained as monolayer cultures in
RPMI-1640 medium phenol red-free supplemented with 10% (vol/vol) FBS,
2 mM glutamine, and antibiotics (100 IU of penicillin/ml
and 100 µg of streptomycin/ml), as previously described (30, 32).
After subculture of cells, using a mixture of 0.05% trypsin and 0.01%
EDTA, cells were plated at the indicated density in 24-well plastic
culture plates (2 cm2/well) previously treated for 24
h with poly-L-lysine and were allowed to adhere 48 h.
RPMI-1640 medium containing the above-mentioned antibiotics and 2%
(vol/vol) FBS, which had been treated twice with dextran-coated
charcoal to remove endogenous steroids, was used in each experiment.
Fresh medium containing the indicated concentrations of steroids and
EGF was added to the cells every 2 days. At the end of the experiment,
the cells were washed with fresh medium and followed by the addition of
labeled DHT or ADT (10 nM), previously dissolved in the
medium, allowed to incubate for 3 h. The medium was then carefully
removed and the measurement of glucuronide formation was performed. At
the end of the specified period of time, 150 µl of methanol were
added to the cells and plates were left to dry at room temperature in
the absence of light for determination of DNA content as previously
described (30).
Steroid glucuronide analysis
Identification and quantification of the steroid glucuronides
was determined using an HPLC system, enabling the separation of
unconjugated and conjugated forms. Steroid glucuronides formed were
previously identified by liquid chromatography ion spray mass
spectrometry (30).
Northern blot analysis
Total RNA was isolated by the tri-reagent acid phenol method and
quantified by optical density. Ten micrograms of total RNA were
separated on a 1% agarose gel. The samples were transferred to a
nylon-N membrane (Amersham, Oakville, Canada) using 10 x SSC.
Prehybridization (12 h, 42 C) and hybridization (24 h, 42 C) were
performed using a solution containing 40% formamide, 5 x
Denhardt’s reagent, 5 x SSPE, 0.1% SDS, and 100 µg of salmon
sperm DNA. A full-length UGT2B15 complementary DNA (cDNA), radiolabeled
by the random hexamer primer technique in the presence of
(-32P) dCTP, was used as the probe (33). After
hybridization, the blot was washed twice with a solution of 0.1 x
SSC, 0.1% SDS at room temperature for 15 min followed by another two
washes of 20 min at 55 C. The membrane was exposed for 8 days at -80 C
on XAR film with an intensifying screen (Kodak Corp., Rochester,
NY).
Ribonuclease protection assay
To generate a probe specific for UGT2B17, the pBK-CMV-UGT2B17
construct was linearized by EcoRI digestion and a
radiolabeled cRNA probe of 318 bases, from nucleotide 1394 to 1629
including 83 bases from the vector, was generated using T7 RNA
polymerase and [-32P] UTP as described in the
MAXIscript kit (Ambion, Austin, TX). The probe specific for UGT2B15 was
generated as previously described (11). For all the ribonuclease
protection assays, 25 µg of total RNA was hybridized with 200,000 cpm
of the appropriate cRNA probe for 16 h at 42 C. cRNA-RNA hybrids
were digested with 0.5 U RNase A and 20.0 U RNase T1 for 30 min at 37
C, and the protected products were analyzed on a 7 M urea,
6% polyacrylamide gel. The amount of protected probe corresponding to
the bands on the film was quantitated by phophorimaging (Molecular
Dynamics, Sunnyvale, CA).
Production and purification of the fusion protein
Cloning and sequencing of the UGT2B17 cDNA was previously
reported (13). For the expression of a 29-kDa protein from amino acid
sequence between 57 to 300 of UGT2B17 enzyme,
HincII-SacI fragment from UGT2B17 cDNA was
subcloned into the pET23a (Novagen, Madison, WI) prokaryotic expression
vector. The E. coli BL21 cells (Novagen) harboring the
recombinant vectors were grown at 37 C in 1 liter of terrific broth
medium supplemented with ampicillin (100 µg/ml). When the absorbance
at 600 nm reached 0.5–0.6 OD U, the production of the fusion proteins
was achieved by adding 1 mM isopropyl
ß-D-thiogalactopyranoside (IPTG) for 2 h at 37 C.
The cells were harvested by centrifugation at 4 C, for 10 min at
5000 x g. The bacterial pellets were resuspended in 25
ml of a lysis buffer (125 mM Tris-HCl, pH 8.0, 4.6% SDS,
10% ß mercaptoethanol and 20% glycerol) and sonicated until
homogeneity using an ultrasound sonicator. The proteins were separated
on a preparative 12% polyacrylamide gel in the presence of SDS-PAGE,
according to the standard method (34). The gel was washed with water
before staining with a cold solution of 0.25 M KCl. The
appropriate bands were excised from the gel and incubated for 2 h
at room temperature and for 16 h at 4 C in a solution containing
500 mM Tris-HCl, pH 7.5. The solutions were centrifugated
for 10 min at 2000 x g, and the resulting supernatants were
lyophilized and resuspended in 5 ml of water, followed by two rounds of
dialyses for 4 h at room temperature and 16 h at 4 C using 50
mM Tris-HCl, pH 7.5 and 50 mM Tris-HCl, pH 7.5,
150 mM NaCl.
Immunization procedure
The rabbits (Charles River Inc., Québec, Canada) were kept
in separate cages in an environmentally controlled room. They were
injected sc at multiple sites with 500 µl of a total of 100 µg of
purified fusion protein in phosphate buffered saline, in the presence
of 500 µl of complete Freund’s adjuvant. Two booster injections were
given at 6-week intervals with the same quantity of protein in the
presence of incomplete Freund’s adjuvant. The production of antibodies
was checked 12 days after each injection on blood collected by ear
puncture.
Immunoblot analysis
To gain information concerning the novel anti-UGT2B17
antibodies, microsomes from the HK293 cells, the stable HK293-UGT2B17
and UGT2B15 cells and from treated LNCaP cells were purified using a
standard method (35). Ten micrograms of each microsomal protein and one
hundred nanograms of the E. coli BL21 pLys S (Novagen)
strain expressing or not the fusion protein were separated on a 12%
SDS-PAGE gel. The gel was transferred onto a nitrocellulose filter and
probe with a dilution 1:2000 of the rabbit antiserum. Antirabbit IgG
horse peroxidase conjugates (Amersham, Oakville, Canada) was used as
secondary antibodies, and the recognized proteins were then visualized
using enhanced chemiluminescence (Renaissance, Québec, Canada)
and exposed on a hyperfilm for 1 h (Kodak Corp., Rochester, NY).
One hundred nanograms of E. coli BL21 (pLys S) cell lysate
containing the 35-kDa recombinant UGT2B17 fusion protein were used to
demonstrate the reactivity of the EL-95 polyclonal antibody.
Protein stability analysis
The UGT2B15 and UGT2B17 stable cell lines were obtained as
previously reported (13, 14). Cells were plated at a density of 5
x 106 cells in 10-cm Petri dishes and treated with 20
µg/ml of cycloheximide for 12 and 24 h. After treatment with
cycloheximide, cells were washed with TBS and homogenized to determine
the enzymatic activity using 500 µM of eugenol as
substrate. Subsequently, if the level of UGT activity was affected by
the treatment, the cell extracts were incubated for 3, 9, 14, and
28 h using the same conditions to determine specifically the
protein half-life. The enzymatic reactions were performed with 100
µM of UDPGA for 30 min at 37 C with 100 µg of proteins.
The glucuronide formation were measured as previously described
(13).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, incubation with EGF
led to increased cell proliferation, and this effect was additive when
cells were treated with both EGF and 0.5 nM of DHT. To
determine the effect of EGF on UGT activity in LNCaP cells, the level
of DHT-G secreted into the cell media was measured after the incubation
with labeled substrate. EGF decreased the level of DHT-G in a
dose-dependent manner where the glucuronidation of DHT was inhibited by
36, 47, and 51% in the presence of 1, 10, and 100 ng/ml of EGF,
respectively. Treating LNCaP cells with 0.5 nM of DHT
decreased DHT-G formation by 43%, and the incubation of cells with a
combination of both EGF and DHT caused an additive inhibitory effect on
UGT activity (Fig. 1B). The same results were obtained when using ADT
as substrate (data not shown).
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). As well, incubating the cells with a specific
antibody against the EGF receptor (38), which has previously been shown
to block EGF binding, also reduced the inhibitory effect of EGF on DHT
glucuronidation.
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). Furthermore, a greater inhibition was observed in
the presence of both the androgen and the growth factor. As shown on
the Northern blot in Fig. 3, the UGT2B15 probe hybridizes to
transcripts of approximately 2.1 kb and 2.3 kb, which indicates the
presence of at least two different UGT mRNAs. Treatment of LNCaP cells
with DHT and EGF led to a preferential decrease of the lower band at
2.1 kb, while the upper band at 2.3 kb persisted.
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). The
level of UGT2B15 transcript in LNCaP cells was not affected by EGF and
DHT (Fig. 4A), however, the level of UGT2B17 transcript was decreased
by 46, 84, and 91%, when cells were treated with 0.5 nM of
DHT or 10 ng/ml of EGF and a combination of both compounds,
respectively.
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, the UGT2B17 antisera specifically recognizes the
29-kDa fusion protein expressed in E. coli BL21 cells. As
expected, an antibody specific for the T7-Tag in the fusion protein
also recognizes the 29-kDa protein. Western blot analyses with
microsomes isolated from HK293 cells stably expressing UGT2B17,
demonstrated the presence of the 53 kDa UGT2B17 protein as expected.
Similar analysis with microsomes from untransfected cells and cells
expressing UGT2B15, revealed some minor bands that are probably due to
cross-reactivity.
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). Incubation with both DHT and EGF decreased the
level of UGT2B17 by 75%; however, this inhibitory effect was partially
alleviated by treatment with tyrphostin A46.
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). The level
of UGT2B15 activity was not affected after 24 h of cycloheximide
treatment; however, the level of UGT2B17 activity was significantly
reduced indicating the higher lability of this protein. To obtain an
estimate of the UGT2B17 protein half-life, cycloheximide treatments
were subsequently performed for 3, 9, 14, and 28 h and 50% of the
activity was lost after approximately 3 h (Fig. 7B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-reductase and 3-hydroxysteroid dehydrogenase) involved in
steroid metabolism, are regulated by androgens and growth factors (26, 28, 42, 43, 44, 45). As well, it has been shown that androgens can also alter
the activity of UGT enzymes, which are involved in steroid catabolism,
in LNCaP cells (32). The expression of EGF and the EGF-receptor has been demonstrated in the human prostate and in LNCaP cells (18, 19, 41, 45, 46), and cell proliferation was stimulated both in vivo and in vitro by several growth factors, including EGF (19, 46, 47, 48, 49, 50). The action of EGF to increase the proliferation of LNCaP cells is observed when cells are incubated with 1–100 ng/ml of the growth factor. Androgens and EGF have been shown to have similar effects in LNCaP cells where they promote increased cell proliferation and inhibit the level of the androgen receptor and the secretion of PAP. However, these effectors can also have opposite effects where EGF decreases the secretion of PSA while androgens increase its secretion (36, 51, 52), which suggests that EGF in prostate cells does not function by activation of the androgen response pathway. Another common effect of EGF and androgens in LNCaP cells is their inhibition of androgen glucuronidation. Treatment of LNCaP cells with either EGF or DHT reduces the formation of glucuronidated DHT and ADT, and a combined treatment of both effectors leads to a greater decrease of glucuronidated androgens. The lowered glucuronidation of DHT and its metabolites leads to an increased level of active androgens in the cells and can play a role in the observed increase of cell proliferation in response to androgens and EGF.
Although the inhibitory effect of androgens and EGF on UGT enzymes may
be mediated through different signal transduction pathways, there is
evidence of cross-talk between these two pathways (52). As an example,
the recent observation that an androgen response can be activated by
EGF in an androgen-depleted environment strongly suggests the
interaction of growth factors with the androgen-signal transduction
cascade in prostatic tumor cells (53). As observed in the present
study, both DHT and EGF are capable of inhibiting androgen
glucuronidation via different mechanisms and appear to be synergistic.
The action of EGF was blocked by tyrphostin A46 and an
anti-EGF-receptor antibody; however, they did not alter the inhibitory
effect of DHT. Furthermore, treating LNCaP cells with DHT and EGF
caused the largest decrease of UGT2B17 protein; however, the addition
of tyrphostin A46 restored the level of UGT2B17 protein to that seen
with the DHT treatment alone (Fig. 6
). Lyall et al. (37)
have demonstrated that tyrphostin A46 can specifically inhibit
EGF-stimulated receptor autophosphorylation and tyrosine
phosphorylation of intracellular endogenous substrates. To further
suggest that EGF and DHT inhibits androgen glucuronidation by different
pathways, we recently observed that the antiandrogen Casodex, which is
known to block androgen binding to its receptor in LNCaP cells (54),
diminished the inhibitory effect of DHT on androgen glucuronidation
(32), but had no effect on EGF action (unpublished data, Guillemette
et al.).
The two isoforms UGT2B15 and UGT2B17 can glucuronidate 5-reduced
C19 steroids; however, it is apparent that UGT2B17 is the
predominant enzyme for glucuronidating androgens in LNCaP cells. RNase
protection analyses demonstrate that the level of UGT2B17 transcript is
decreased in the presence of DHT and EGF; however, these effectors did
not change the level of UGT2B15 mRNA. As expected, the effect of DHT
and EGF was also observed at the protein level, where the decrease of
UGT2B17 protein by 75% correlated with the decreased production of
DHT-G by 73%. When the stability of the UGT2B15 and UGT2B17 proteins
was assessed, it was apparent that UGT2B17, with a half-life of
approximately 3 h, is much more labile than UGT2B15 that did not
decrease in activity in LNCaP cells after incubation with cycloheximide
for 24 h. The more rapid turnover of UGT2B17 indicates that the
observed regulation by DHT and EGF to decrease the level of UGT2B17
mRNA in prostate cells would rapidly reduce the level of UGT2B17
protein and subsequently alter the concentration of androgens.
It is apparent that the regulation by DHT and EGF occurs before protein translation and may be at the level of gene transcription. In the rat UGT2B1 and UGT2B2 genes, hormone responsive elements for steroid nuclear receptor binding were not found in the 5'-flanking region of the genes (55, 56). However, the presence of putative DNA binding sites for activating protein-1 (AP-1) was reported. Interestingly, growth factor receptor activation has been shown to induce AP-1 expression, and interactions between AP-1 proteins (c-Fos and c-Jun) and steroid hormone receptors have been reported (57, 58, 59, 60). To date, the transcriptional regulation of human UGT2B gene expression has not been characterized. Because there is evidence that transcription of a gene can be regulated by different signal transduction pathways, the implication of one or more common factors in the regulation of UGT by androgens and EGF is also possible and may explain the similar inhibitory effect observed.
In conclusion, an important finding from the present study is that
several factors involved in the regulation of tumor proliferation and
progression, can regulate UGT2B17 expression. The inhibitory effect of
androgens and growth factors on androgen glucuronidation may enhance
the proliferation of androgen-dependent tumors because a decrease in
the glucuronidation of DHT or its 5-reduced metabolites can favor an
accumulation of DHT. In addition, our data strongly suggest that
UGT2B17 represents an important key element in the pathway of steroid
metabolism in extrahepatic steroid target tissues.
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Acknowledgments |
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Footnotes |
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2 These authors contributed equally.
3 Holder of a scholarship from the MRC of Canada.
Received December 23, 1996.
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