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Laboratory for Cancer Medicine and University Department of Medicine (B.B.Y., P.J.L.), University of Western Australia; Royal Perth Hospital, Perth, Western Australia 6000; Flow Cytometry Unit (R.G.K.), Royal Perth Hospital, Perth, Western Australia 6000
Address all correspondence and requests for reprints to: Dr. Peter J. Leedman, University Department of Medicine, 4th Floor, Medical Research Foundation Building, Rear, 50 Murray Street, Perth, Western Australia 6001. E-mail: peterl{at}cyllene.uwa.edu.au
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Breast cancer in women provides a complementary model of hormone-responsive cancer. Expression of estrogen receptors (ERs) in breast cancer tissue correlates with responsiveness to hormonal therapy and improved prognosis (18, 19). AR expression in breast cancer tissue samples has been associated with an improved response to hormone therapy and longer survival in patients with breast cancer (20, 21). The AR is detectable in the majority of tumor specimens from patients undergoing mastectomy for breast cancer, AR and ER tending to be coexpressed (22). Recent in vitro studies have demonstrated direct and indirect growth inhibitory effects of androgen on several AR positive (AR+) breast cancer cell lines (23, 24, 25, 26, 27), suggesting an independent effect of androgens, via the AR, on breast cancer progression. Consequently, it would be of interest to establish whether mechanisms underlying the regulation of AR gene expression differ between prostate compared with breast cancer cells.
The AR is autoregulated by androgen, which reduces AR messenger RNA (mRNA) in both rat tissues and LNCaP cells (28, 29, 30). Repression of AR mRNA expression in LNCaP cells has been attributed to reduced transcription with AR mRNA stability being paradoxically increased (31). However, different authors have found conflicting effects of androgen on AR protein expression, ranging from an increase in absolute AR protein content (30), to either posttranslational modification without alteration in AR protein level (31) or stabilization of the AR protein (32, 33). Androgens down-regulate AR mRNA in the T47D and MDA453 breast cancer cell lines (34, 35), but no data are available for the effect of androgens on AR mRNA transcription or stability in breast cancer cells. We used LNCaP and MDA453 cells to determine the relative importance of transcriptional and posttranscriptional mechanisms on androgen regulated AR gene expression in both prostate and breast cancer cells. Our work in LNCaP cells shows that androgens regulate AR mRNA transcription and mRNA turnover for a net decrease in AR mRNA, accompanied by increased AR protein expression and cellular proliferation. Remarkably, however, in MDA453 cells, despite producing a similar increase in AR protein expression, androgens have no effect on transcription and induce an opposite effect on AR mRNA turnover and cellular proliferation. These studies provide novel insight into the differential regulation of AR gene expression in each tumor cell type and establish a central role for posttranscriptional events in the process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell proliferation and cell cycle analysis
For cell proliferation assays, cells were trypsinized and
counted using an automated hematology analyzer (Technicon H1, Technicon
Instruments Corp., Tarrytown, NY). For cell cycle analysis, DHT-treated
and control cells were harvested by trypsinization, permeabilized, and
stained for DNA overnight at 4 C in 0.2% Triton X-100 with 50 µg/ml
propidium iodide. RNase A 100 µg/ml was added at room temperature
2 h before analysis by flow cytometry (Coulter EPICS XL-MCL,
Beckman Coulter, Inc., Hialeah, FL). MultiPlus AV
MultiParameter Data Analysis Software (Phoenix Flow Systems, San Diego, CA) was used to determine the proportion of
cells in the various phases of cell cycle.
Northern analysis
For RNA extraction, cells were lyzed in a buffer containing 4
M guanidinium thioisocynate, 0.5% lauroylsarcosine, 25
mM Na citrate, pH 7.0, 0.2 M Na acetate, pH
4.1, and 4 mM 2-mercaptoethanol followed by
phenol-chloroform extraction and isopropanol precipitation. Northern
gel electrophoresis was performed with 10–12 µg total RNA per lane
in a denaturing gel in 1 x MOPS buffer followed by overnight blot
transfer in 10 x SSC to nylon membrane (Hybond N+, Amersham Life Sciences, Little Chalfont, Buckinghamshire, UK). A
linearized Bluescript vector containing the 713 bp
HindIII/EcoRI fragment (nucleotides 1850 to 2563)
of the AR complementary DNA (cDNA) sequence (36) was used to synthesize
a 32P-labeled complementary RNA (cRNA) probe using the T7
RNA polymerase promoter in a 10-µl reaction mix containing 100 µCi
32P UTP (Amersham Life Sciences), 1 µg
linearized plasmid, 1 x transcription buffer, 0.5 mM
ATP, CTP, GTP, 20 mM dithiothreitol (DTT), 40 U RNAsin, and
19 U T7 RNA polymerase (Promega Corp., Madison, WI) at 37
C for 45 min. Hybridization was performed overnight at 65 C in 50%
formamide, 5 x SSC, 5 x Denhardt’s solution, 5% SDS, 50
mM NaPO4, pH 7.0, and 500 µg/ml yeast RNA
followed by sequential washes in 1 x SSC/1% SDS, 0.5 x
SSC/0.5%SDS and 0.1 x SSC/0.1% SDS. A predominant AR mRNA of
10.5 kb was detected, as described previously. Membranes were stripped
and reprobed with a rat 18S ribosomal RNA cDNA probe as a loading
control. Quantitation was performed using a PhosphorImager 445 SI with
ImageQuant software (Molecular Dynamics, Inc., Sunnyvale,
CA).
Nuclear run-on assays
Nuclei were prepared by washing cells in ice-cold PBS followed
by two rounds of lysis in a buffer containing 10 mM
Tris-HCl, pH 7.5, 10 mM NaCl, 3 mM
MgCl2 and 0.5% Nonidet P-40 and centrifugation at 800 rpm
for 5 min at 4 C. The final pellet of 5–10 x 106
nuclei was resuspended in a 100 µl volume of 50 mM
Tris-HCl, pH 8.3, 40% glycerol, 0.1 mM EDTA, and 0.1
mM DTT and stored at -80 C. Transcription was performed in
a 200 µl volume of nuclei in 5 mM Tris-HCl, pH 7.5, 2.5
mM MgCl2, 150 mM KCl, 50
mM DTT, 0.5 mM each of ATP, CTP, GTP, and 100
µCi 32P UTP for 30 min at 30 C. Labeled RNA was
phenol-chloroform extracted in GTC/Na acetate with 30 µg/ml yeast
transfer RNA and precipitated with isopropanol before resuspension in
10 mM TES
(N-Tris(Hydroxymethyl)methyl-2-aminoethanesulfonic acid), pH
7.4, 10 mM EDTA, 0.2% SDS and 0.3 M NaCl.
Amersham Life Sciences Hybond N+ filters were slot blotted
with an excess of detection cDNA probes (10 µg 3.1 kb AR cDNA
sequence in linearized pBluescript vector, 2.5-µg, 1.1-kb r18S
plasmid, and 10 µg 1.3-kb GAPDH plasmid in separate slots for
normalizing controls). Hybridization was performed in 50% formamide,
5 x SSC, 5 x Denhardt’s solution and 1% SDS at 42 C for
48 h.
Western immunoblotting
Cells were lysed in a buffer containing 0.5% deoxycholic acid,
0.5% SDS, 0.5% Nonidet P40, 50 mM NaCl, 10 mM
Tris, pH 7.6, 10 µg/ml aprotinin, and 1 mM
phenylmethylsulfonyl fluoride before centrifugation at 13,000 rpm for
10 min at 4 C and storage in aliquots at -80 C. Protein concentration
was quantitated in triplicate using the Bio-Rad Laboratories, Inc. (Hercules, CA) assay dye and Microplate Reader 450 at a
wavelength of 595 nm. SDS-PAGE was performed using 20 µg of protein
lysate per lane followed by blot transfer onto nitrocellulose membrane
(Optitran BA-S 85, Schleicher & Schuell, Inc., Dassel,
Germany) in Tris 20 mM, glycine 150 mM,
methanol 20%, and SDS 0.02%. Membranes were blocked with 5% skim
milk powder in TBS-T (20 mM Tris, pH 7.4, 150
mM NaCl, 0.1% Tween-20) before sequential incubations with
rabbit polyclonal antibody to human AR in a 1:1000 dilution (Signet
PG21, Dedham, MA) and HRP conjugated secondary antibody in a 1:2000
dilution (Sigma Chemical Co.). Enhanced chemiluminescence
(ECL) was performed with Amersham Life Science ECL Western
blotting detection reagents according to the manufacturer’s protocol.
For a loading control, blots were washed in TBS-T and reprobed with a
mouse polyclonal antibody to poly(A)-binding protein (PABP) (37) in a
1:600 dilution followed by HRP conjugated mouse secondary antibody in a
1:20,000 dilution (Sigma Chemical Co.) before ECL using
the Amersham Life Science ECL Plus protocol.
35S-labeling and immunoprecipitation
Cells were prepared for experiments as above. After a 5-h
incubation in the presence or absence of DHT 10 nM, the
media were aspirated, cells were washed with PBS and replaced with
methionine-free, phenol red-free RPMI medium 1640 with 10% DCS
FCS and antibiotics ± DHT for 2 h. We added 200 µCi/ml
35S methionine (Promix, Amersham Life Sciences) harvested cells after 1 h of 35S
incorporation by twice washing in cold PBS and lysis as described
previously. A 2 x 107 cpm protein lysate was used for
immunoprecipitation overnight at 4 C with AR antibody at a dilution of
3:500 followed by addition of protein A Sepharose beads (1:10 volume,
Pharmacia Biotech, Uppsala, Sweden). Beads were washed
three times in lysis buffer, once in cold PBS, and boiled for 4 min in
80 mM Tris, pH 6.8, 7.5% glycerol, 2% SDS, 0.2%
mercaptoethanol, and 24 µg/ml bromophenol blue before SDS-PAGE.
Additional experiments were performed using the rabbit polyclonal AR
antibody AR52 (32).
Data analysis and statistics
Statistical analysis was performed using General Linear
Models. ANOVA was performed to assess the significance of
treatment (DHT) x time interactions. Where appropriate, means
comparisons at specific time points were made using Student’s
t test. A P value of less than 0.05 was
considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(ER) and progesterone receptor (35). Thus, these two
cell lines provide an ideal comparative system to identify differences
in the mechanisms involved in androgen-induced regulation of AR gene
expression. We first sought to characterize the effect of DHT on LNCaP
and MDA453 cell proliferation. LNCaP cells were seeded in equal density
in identical tissue culture plates and cultured in 10% DCS FCS for
48 h before the addition of DHT with control cells maintained in
androgen-depleted condition. Media were replaced at the time of hormone
addition and then left for the duration of the experiment. DHT-treated
and control cells were harvested and counted at progressive time points
to determine the effect of DHT on cell proliferation. In LNCaP cells,
DHT 10 nM significantly increased cell proliferation
(ANOVA; DHT x time interaction 0–72 h: P =
0.002, means comparison after 72 h: P < 0.01),
consistent with the androgen dependence of LNCaP cells (38, 40, 41)
(Fig. 1A
). A comparable proliferative
effect of DHT was demonstrable in LNCaP cells at a 1 nM
concentration (data not shown). A similar protocol was employed in
MDA453 cells with a shorter 24 h period of growth in media with
10% DCS FCS before addition of DHT to prevent the faster growing
MDA453 cells from becoming overconfluent during the course of
experiments. In MDA453 cells, DHT 10 nM reduced cell
proliferation (Fig. 1B). The effect of DHT appeared to be greatest
after 24 h (means comparison at 24 h: P =
0.005) with a lesser effect thereafter (ANOVA; DHT x time
interaction 0–72 h: P = 0.07). The more rapid
proliferation of MDA453 cells both in the absence and presence of DHT
compared with DHT-treated and control LNCaP cells reflects the faster
growth of the MDA453 cell line. To extend these observations, we
analyzed the effect of androgen on cell cycle progression. Androgen
deprivation resulted in a low proportion of LNCaP cells in S-phase of
the cell cycle. DHT 10 nM significantly increased the
proportion of LNCaP cells in S-phase by greater than 2-fold (Fig. 2A). In marked contrast, in MDA453 cells
DHT 10 nM significantly reduced the percentage of cells in
S-phase of the cell cycle (Fig. 2B). The faster growth of the MDA453
cells in 10% DCS FCS was reflected by the greater proportion of these
cells in S-phase of cell cycle both in the presence and absence of DHT.
These observations indicate differential effects of androgens on cell
proliferation and cell cycle modulation in these two cell types. DHT
increases LNCaP cell proliferation by increasing the proportion of
cells actively engaged in mitosis and inhibits MDA453 cell
proliferation by reducing the proportion of cells entering S-phase of
the cell cycle.
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). The major message was located at
10.5 kb, and this band was used for subsequent quantitation of AR mRNA.
Incubation of the cells with DHT 10 nM significantly
decreased steady-state AR mRNA (10.5 kb band) with AR mRNA levels at 2
and 8 h being 60 and 55% of levels found in control cells,
respectively (Fig. 3B). This decrease was maintained at 24 and 48
h (70 and 45% of control, respectively) with some loss of effect
apparent by 72 h (Fig. 3B) (ANOVA; DHT x time interaction
0–48 h: P = 0.001). When DHT 1 nM was
used, down-regulation of AR mRNA to 75% of control was found with
similar loss of effect occurring at 72 h (data not shown). Similar
down-regulation of AR mRNA was found when the synthetic androgen
mibolerone at doses of 3.3 and 10 nM was substituted for
DHT, except that down-regulation persisted at 72 h (data not
shown). The 10 nM concentration of DHT gave optimal
responses for AR mRNA and was thus continued for subsequent
experiments, its effects on cell proliferation and cell cycle
modulation having previously been determined. MDA453 cells were
cultured in identical conditions and left in androgen-free conditions
for 24 h before the addition of DHT. A similar effect was noted in
MDA453 cells with a decrease in AR mRNA to 60% of control levels after
8 and 24 h incubation with DHT 10 nM (ANOVA; DHT
x time interaction 0–24 h: P = 0.04) (Fig. 3C).
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). A lesser effect of DHT was found
after 24 h treatment with DHT (Fig. 4A). In contrast, there was no
effect of DHT on AR mRNA transcription in MDA453 cells similarly
treated for 8 h with comparable quantities of AR mRNA synthesized
both in the presence and absence of DHT (Fig. 4B). These data confirm
the contribution of DHT-induced transcriptional down-regulation in
LNCaP cells. However, the data also suggests that in MDA453 cells, DHT
was modulating AR mRNA predominantly via posttranscriptional changes in
AR mRNA turnover.
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shows that AR mRNA half-life in LNCaP
cells was significantly increased in the presence of DHT by greater
than 2-fold from 5.5 to >12 h (ANOVA; P < 0.001). The
DHT induced approximately 2-fold stabilization of AR mRNA was observed
with preincubation times for DHT 10 nM of 2 and 8 h
before addition of Act D. In contrast to the stabilization of AR mRNA
documented in LNCaP cells, in MDA453 cells, AR mRNA half-life was
significantly reduced from 3 h in control cells to 2 h in
cells treated with DHT 10 nM for 8 h before addition
of Act D (ANOVA; P < 0.001) (Fig. 5B). Thus, androgens
induced divergent effects on AR mRNA turnover in these two cell lines.
In conjunction with the transcriptional data, these results suggest
fundamental differences in the mechanisms underlying AR mRNA
autoregulation by androgen in these two cell types. In LNCaP cells, the
down-regulation of steady-state AR mRNA by DHT occurs at the
transcriptional level. In MDA453 cells, the effect of DHT to
down-regulate AR mRNA expression results primarily from
posttranscriptional destabilization of AR mRNA.
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). Blots were washed and reprobed with
an antibody to the 70-kDa PABP as a loading control (37). Treatment of
LNCaP cells with androgen resulted in a 2- to 3-fold increase in AR
protein, maximal after 8 h of DHT and reducing after 24 h
(means comparisons; 8 h P < 0.001, 24 h
P = 0.01: DHT > control) (Fig. 6B). A similar
increase in AR protein levels was seen in DHT treated MDA453 cells
(means comparisons; 8 h P = 0.047, 24 h
P = 0.005: DHT > control) (Fig. 6C). The
parameters of the SDS PAGE allowed quantitation of immunoreactive AR
protein but did not provide sufficient size resolution to show protein
mobility shifts from androgen induced AR phosphorylation (42, 43).
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). In MDA453
cells treated under identical conditions, DHT did not alter the
quantity of labeled immunoprecipitated AR protein (Fig. 7B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In LNCaP cells, the reduction in AR
mRNA occurs in the presence of AR mRNA stabilization. Thus, the
transcriptional down-regulation that occurs predominates over the
reduction in AR mRNA turnover at that point in time (8 h). However,
this mechanism is cell specific and is not the case for MDA453 cells.
Instead, in MDA453 cells, posttranscriptional destabilization of AR
mRNA provides an equally rapid and significant down-regulation of AR
mRNA, in the absence of simultaneous transcriptional change (Fig. 8B).
These results demonstrate the cell-specific, divergent nature of
posttranscriptional regulation of AR mRNA by androgen and establishes
that AR mRNA destabilization is the major determinant of steady-state
AR mRNA expression in MDA453 cells under these conditions.
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We found rapid down-regulation of AR mRNA by DHT with concomitant increases in AR protein expression occurring within 8 h of exposure to androgen in both LNCaP and MDA453 cells. These results differ from the slower time course of AR mRNA down-regulation by DHT or mibolerone previously reported in LNCaP cells (40- to 96-h incubations) (30, 31). With regard to AR protein expression, Krongard et al. (30) found a 2-fold increase in immunoreactive AR protein, an increase in ligand binding, and a protein gel mobility shift in androgen treated LNCaP cells. Wolf and colleagues (31) found no change in AR protein levels, noting instead an alteration in protein mobility, suggesting posttranslational modification or phosphorylation (43). However, we found a significant, rapid increase in AR protein expression occurring within 8 h of treatment with DHT. The earlier time course response may account for the lack of alteration in AR protein levels after 96 h incubation with mibolerone (31) when the androgen response may have diminished. Additionally, DHT 10 nM may represent an optimal concentration of ligand to use in tissue culture conditions to demonstrate regulation of both AR mRNA and AR protein. Given the rapid increase (in LNCaP cells) or decrease (in MDA453 cells) in the number of cells in S-phase of cell cycle occurring within 24 h of androgen exposure, short incubation times with androgens may be more physiologically relevant in these tumor cells.
The quantity of 35S-labeled, immunoprecipitated AR that we observed is determined by the rate of de novo synthesis and subsequent degradation of AR protein within the 60-min period of 35S-methionine incorporation. The slight enhancement of AR signal in DHT-treated LNCaP cells implies that no large increase in AR synthesis occurs as a result of DHT treatment (unless a concomitant more rapid degradation also takes place). Thus, we believe that the increased steady-state AR protein levels found in DHT treated LNCaP and MDA453 cells on Western immunoblotting is most likely a result of stabilization of the ligand receptor complex by ligand binding, as has been previously described (32, 33). As similar increases in AR protein expression with DHT were found in LNCaP and MDA453 cells despite different effects of DHT on cellular proliferation and cell cycle modulation, androgen-induced alterations in the number of ARs alone does not appear to mediate proliferative as opposed to inhibitory effects on growth. Rather, AR target genes or AR-related transcriptional coactivators and/or corepressors influencing growth and cell cycle progression might be differentially expressed in prostate compared with breast cancer cells.
In LNCaP cells, DHT from 1 to 100 nM exerts a proliferative effect lost at lower or higher concentrations of DHT (38), emphasizing the importance of selecting an appropriate ligand concentration for experiments. Previous work has utilized up to 10–20 nM DHT and between 1 to 10 nM mib for AR mRNA regulatory experiments in LNCaP cells (30, 31). We found that DHT 10 nM produced divergent proliferative and cell cycle responses in LNCaP compared with MDA453 cells. This concentration was used consistently in our experiments examining regulation of AR gene expression in the two cell types.
The divergent effect of androgen on AR mRNA turnover in these cell lines suggests that very different mechanisms are involved in maintaining AR mRNA stability. Previous work has shown stabilization of AR mRNA in LNCaP cells by mibolerone (31). In ventral and dorsal lobes of the rat prostate, up-regulation of AR mRNA on androgen withdrawal occurred without any alteration in AR gene transcription, suggesting posttranscriptional stabilization (51). Posttranscriptional destabilization of AR mRNA in the absence of transcriptional change by androgens in MDA453 cells thus appears to be a novel mechanism of AR mRNA autoregulation. Interactions between specific sequences within mRNA (cis-acting elements) and cellular RNA-binding proteins (trans-acting factors) as well as ribonuclease activity targeting the mRNA, are factors that determine the rate of mRNA turnover (52, 53, 54, 55). Thus, differentially expressed androgen-regulated RNA binding proteins might influence AR mRNA stability. The differences in androgen-regulated AR mRNA half-life in LNCaP compared with MDA453 cells are strongly suggestive of the existence and differential expression of such trans-acting factors. However, little is known of the identity of cis-acting elements and trans-acting factors for AR mRNA. Identification and cloning of such cellular trans-acting factors and determination of their functional role in relation to AR mRNA stability would be an important advance in further understanding the mechanism of androgen-regulated AR gene expression in these cancers. Furthermore, it would allow exploration of new therapeutic interventions based on targeted disruption of specific cellular cis-trans RNA-protein interactions (56).
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Acknowledgments |
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Footnotes |
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Received October 13, 1998.
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