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B Signaling by the Androgen Receptor Facilitates 12-O-Tetradecanoylphorbolacetate-Induced Apoptosis in Androgen-sensitive Prostate Cancer LNCaP Cells
George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology, University of Rochester Medical Center, Rochester, New York 14642 [S. A., H-K. L., K-H. C., S. Y., W-J. L., L. A. H., M. M. R., L. Y., Y. Z., C. C.], and Graduate Institute of Clinical Medical Sciences and Center for Menopause and Reproductive Medicine Research, Chang Gung University, Taiwan 833, Republic of China [H-Y. K., M-Y. T.]
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ABSTRACT |
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-dihydrotestosterone (DHT)/TPA-induced apoptosis, suggesting that DHT/TPA-induced apoptosis is mediated by androgen/androgen receptor (AR). In addition, a caspase-3 inhibitor (Ac-DEVD-CHO) reduced the level of apoptosis, suggesting that DHT/TPA-mediated apoptosis occurs through a caspase-3-dependent pathway. A functional reporter assay using nuclear factor (NF) 
B-luciferase and an electromobility gel shift assay showed that DHT suppressed NFB activity. In addition, apoptosis mediated by combined DHT/TPA treatment was abrogated by overexpression of the NFB subunit p65 in LNCaP-p65 cells, suggesting that NFB may play an important role in regulating the effects of androgen/AR and TPA on apoptosis. Furthermore, use of the c-Jun N-terminal kinase (JNK) inhibitor SB202190 showed that the combination of DHT/TPA increased JNK activation in LNCaP cells but not in LNCaP-p65 cells, demonstrating that NFB may be able to suppress JNK activity. These results indicate that androgen/AR facilitates TPA-induced apoptosis by interruption of the NFB signaling pathway, leading to activation of JNK in LNCaP cells. These data describe a signaling pathway that could potentially be useful in proposed therapeutic treatment strategies exploiting combinations of different agents that control apoptosis in prostate tumors. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Intermittent androgen therapy has been proposed as a means to minimize adverse effects associated with androgen ablation therapy. Repeated cycles of intermittent treatment may postpone the emergence of androgen-independent tumor cells, decrease the severity of advanced treatment-related effects, and be less costly than continuous androgen-ablative therapy. It has been hypothesized that reintroduction of androgen after a period of androgen deprivation may alter the growth behavior of the remaining tumor cells (5 , 6) , an effect that may be caused, in part, by alterations in the apoptotic potential of remaining tumor cells in the presence of emergent androgen levels. The effect of intermittent androgen therapy has been studied in animals, but the molecular mechanisms controlling the delay to androgen independence are poorly understood. Because apoptosis may play a role in such processes, an understanding of the contribution of androgen/AR2 to apoptosis induction is important in developing a rationale for exploitation of such therapeutic approaches.
Characterization of the role of AR in controlling apoptosis and the participation of AR signaling in cross-talk with other pathways will clarify the role of androgen in prostate tumor growth. Induction of apoptosis is determined by the integration of numerous signals that control entry into the cell death pathway. One pathway that controls cell growth and differentiation is activation of PKC (7
, 8)
. Activation of PKC by TPA induces apoptosis in the androgen-sensitive cell lines LNCaP (9)
and HaCaT (10)
but not in the androgen-independent cell lines PC-3 and DU145 (9)
, or in normal keratinocytes (10)
. Another pathway involved in growth control and suppression of apoptosis involves NFB, which is a member of the nuclear transcription factor family of proteins (11)
. NFB consists of dimers of Rel family proteins (12
, 13)
, each of which contains a conserved Rel homology domain that allows dimerization and a DNA binding domain that allows binding to NFB response elements on the target genes. In mammalian cells, there are five members of the NFB family: NFB1 (p50/p105), NFB2 (p52, p100), RelA (p65), cRel, and RelB (12)
. NFB is retained in the cytoplasm in an inactive form by the inhibitor protein IB (14
, 15)
. In response to certain extracellular signals such as TNF, interleukin-1, TPA, or lipopolysaccharide (16
, 17)
, IKK is activated and phosphorylates IB, releasing NFB, which then translocates to the nucleus and binds to DNA.
It has been reported that NFB induces expression of target genes that contribute to tumor progression. These genes include immunoregulatory, inflammatory, and antiapoptotic genes as well as genes that regulate cell proliferation (18)
. In the androgen-independent prostate cell lines PC-3 and DU145, the activity of NFB is high compared with that in the androgen-dependent prostate cell line LNCaP (19)
. It has also been shown that in LNCaP cells cross-talk occurs between NFB signaling pathways and steroid receptor signaling pathways, such as glucocorticoid receptor and AR pathways (20, 21, 22)
. Differences in NFB activity between androgen-sensitive and androgen-independent prostate cancer cell lines may contribute to androgen independence (23)
.3
Moreover, when cells undergo apoptosis, JNK activity is increased (24
, 25)
. Recent studies have shown that cross-talk exists between the JNK and NFB signaling pathways (25
, 26)
. It has been proposed that JNK activity is an upstream event relative to activation of caspase cascades during apoptosis.
The differences between androgen-sensitive and androgen-independent cell lines with respect to TPA-induced apoptosis and NFB activity (23)
prompted the hypothesis that TPA may induce apoptosis through an AR-dependent pathway in LNCaP cells. To define the role of androgen/AR in apoptosis signaling in LNCaP cells, we used a regimen of treatment with androgen for 24 h, followed by 24-h treatment with 1 nM TPA. To characterize the response of LNCaP cells to these treatment conditions, we determined the percentage of cells undergoing apoptosis and the activities of AR, NFB, caspases, and JNK in the apoptotic cascade. Our data show that interruption of NFB signaling by androgen/AR facilitates TPA-induced apoptosis via activation of JNK. This observation suggests that androgen pretreatment sensitizes cells to the apoptotic effect of PKC activation in a prostate cancer cell line. Resumption of androgen levels during intermittent androgen therapy may sensitize tumor cells to proapoptotic agents, providing an opportunity to improve the effectiveness of intermittent androgen therapy.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B and Anti-Rel (p65) were obtained from Santa Cruz Biotechnology. A monoclonal antiactin antibody was obtained from Amersham Biosciences. The plasmids pCDNA3, pCDNA3-RelA, pCMV, pCMV-mIkB (Ser32–36), and pCMV-NFB Luc reporter gene were gifts from Dr. Edward M. Schwarz (University of Rochester, Rochester, NY).
Detection of Apoptosis.
To visualize apoptotic nuclei, LNCaP cells were fixed in 4% paraformaldehyde (pH 7.4) and subjected to the TUNEL assay. End-labeled DNA was visualized using FITC-conjugated avidin, and total cell count was determined by 4',6-diamidino-2-phenylindole staining. In brief, myocytes were incubated for 1 h at 37°C in terminal deoxynucleotidyltransferase buffer containing 140 mM sodium cocodylate, 1 mM cobalt chloride, 30 mM Tris-HCl (pH 7.2), 50 units of terminal deoxynucleotide transferase, and 1 nmol of fluorescein-conjugated dUTP (Roche Molecular Biochemicals). After the terminal deoxynucleotidyltransferase reaction, cells were washed three times in PBS and mounted on glass slides. The number of FITC-labeled cells per 100 4',6-diamidino-2-phenylindole-stained cells was used as a measure of the percentage of apoptosis. Genomic DNA was isolated for nucleosomal DNA fragmentation by gel electrophoresis, as described previously (28)
.
Transfections and Reporter Gene Assays.
Transfections, using the calcium phosphate precipitation method, and Luc assays were performed as described previously (29)
. Briefly, 1–4 x 105 cells were plated on 35- or 60-mm dishes 24 h before adding the precipitation mix containing an NFB-Luc reporter gene. In each experiment, the total amount of transfected DNA/dish was maintained at a constant level by the addition of an empty expression vector (pCMV). The medium was changed 24 h after transfection, and the cells were treated with 1 nM DHT for 24 h, followed by treatment with TPA for another 16 h. The cells were then harvested, and whole cell extracts were used for the Luc assay. Luc activity was determined using a Dual-Luciferase Reporter Assay System (Promega) and measured with a luminometer.
Western Blot Analysis.
LNCaP cells were treated with 10 nM DHT for 24 h, followed by 24 h of treatment with 1 nM TPA. The medium was removed, and the attached cells were washed with PBS. Proteins were extracted by cell lysis with SDS, and protein concentrations were measured with the BCA protein reagent (Pierce Chemical Co., Rockford, IL). Equal amounts of total protein (50 µg) were loaded and run on a 10% SDS-polyacrylamide stacking gel with a Tris/glycine running buffer system and then transferred to a polyvinylidene difluoride membrane (0.2 µm) in a mini electrotransfer unit (Bio-Rad, Hercules, CA). The blots were probed with anti-AR, anti-RelA, and antiactin antibodies. Immunoblot analysis was performed with horseradish peroxidase-conjugated antirabbit and antimouse IgG antibodies using enhanced chemiluminescence Western blotting detection reagents (Amersham Biosciences).
EMSA.
Nuclear extracts of cells were prepared as described previously (30)
. 32P-radiolabeled duplex oligonucleotide probes containing the NFB consensus binding site 5'-AGTTGAGGGGACTTTCCCAGGC-3' and the mutant sequence 5'-AGTTGAGGCGATTTCCCAGGC-3' were used as templates for EMSA experiments (Santa Cruz Biotechnology). DNA binding reaction mixtures (20 µl) were prepared on ice and contained 10 µg of nuclear extract, 2 µg of double-stranded probe, poly(dI-dC) (Amersham Pharmacia Biotech), and 10 µg of BSA in 20 mM HEPES (pH 7.9), 5% glycerol, 1 mM EDTA, and 5 mM DTT. Nuclear protein complexes were resolved on a native 5% polyacrylamide gel in 1x Tris-borate EDTA (pH 8.0) and detected by autoradiography (30)
.
JNK Assay.
For the JNK kinase assay, subconfluent LNCaP cells were incubated for 24 h in RPMI medium containing 10% charcoal dextran-fetal bovine serum and then stimulated with 10 ng/ml TNF- for 15 min. Total cell lysates were prepared as described previously (31)
, and JNK activity was determined using an anti-phospho-JNK antibody and JNK assay kit according to the manufacturer’s instructions (New England Biolabs). Briefly, GST-c-Jun (aa 1–89) fusion protein bound to glutathione-Sepharose beads was incubated with cell lysates for 2 h at 4°C and then centrifuged at 15,000 rpm for 15 min to pull down JNK. The samples were subjected to SDS-PAGE and transferred to a nitrocellulose membrane. The kinase activity was determined by Western blot analysis of phosphorylated c-Jun using a rabbit anti-phospho-c-Jun antibody.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) or 10 nM DHT (Fig. 1Ab)
for 24 h and then treated with 1 nM TPA for another 24 h (Fig. 1A, c and d)
. Cells were then observed under light microscopy and photographed.
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or 1 nM TPA alone (Fig. 1Ac)
does not induce apoptosis. However, treatment with 10 nM DHT for 24 h, followed by 24-h treatment with 1 nM TPA induced substantial apoptosis as determined by cell morphology (Fig. 1Ad)
and DNA fragmentation (Fig. 1B
, Lane 4). The percentage of cells undergoing apoptosis was determined by TUNEL assay, as described in "Materials and Methods" and shown in Fig. 2A
. These results indicate that androgen/AR enables a lower concentration of TPA to induce apoptosis in LNCaP cells.
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; Refs. 9
, 31
). To show that TPA-induced apoptosis in LNCaP cells is dependent on signaling through the AR, we used the AR antagonist bicalutamide (Casodex) to block the effect of AR signaling. Pretreatment of cells with 1 µM bicalutamide (Casodex) significantly reduced apoptosis induced by the combination of TPA and DHT, as shown in Fig. 2B
. The ability of bicalutamide to prevent >70% of the DHT/TPA-induced apoptotic effect suggests that AR is involved in DHT/TPA-induced apoptosis.
DHT/TPA-induced Apoptosis in LNCaP Cells Is Caspase-3 Dependent.
A number of studies have shown that exposure to radiation in the presence of TPA enhances caspase-dependent apoptosis (8
, 9 , 33)
. We tested whether apoptosis induced by the combination of DHT and TPA involves activation of the apoptotic caspase cascade. Caspase-3 plays a major role in apoptosis, and detection of the activated form of caspase-3 represents apoptotic activity within the cell. We used zVAD-fmk, a general caspase inhibitor, and Ac-DEVD-CHO, a caspase-3 inhibitor, to show the role of caspase activation in the observed apoptotic response. Cells were treated with 10 nM DHT for 24 h and then incubated with either zVAD-fmk or Ac-DEVD-CHO for 30 min, followed by 24-h treatment with 1 nM TPA. Cells were then assayed for apoptosis using a TUNEL assay. The results show that apoptosis was reduced at least 50% by zVAD-fmk and 60% by Ac-DEVD-CHO (Fig. 3A)
, suggesting DHT/TPA-mediated apoptosis is a caspase-3 dependent pathway.
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, Lane 4). These data show that the majority of apoptosis generated by the combination of DHT before treatment and TPA is caspase-3 dependent.
AR Interrupts NFB Signaling in LNCaP Cells.
It is known that TPA is a potent activator of IKK (34, 35, 36)
. It is also known that NFB is capable of protecting cells from apoptosis (37)
. In the androgen-independent prostate cell lines PC-3 and DU145, the activity of NFB is higher compared with the androgen-sensitive prostate cell line LNCaP (19)
. It also has been shown that cross-talk between NFB signaling pathways and steroid receptor signaling pathways, such as those of the glucocorticoid receptor and AR, occurs in LNCaP cells (20, 21, 22)
. To determine the effect of treatment with 10 nM DHT, followed by 1 nM TPA, on NFB activity, we performed a transactivation assay using a Luc reporter construct responsive to active NFB. Treatment with 1 nM TPA alone shows significant activation of NFB (Fig. 4A
, Lane 3). Pretreatment with 10 nM DHT abrogated this activation (Fig. 4A
, Lane 4), indicating an interaction between AR signaling and TPA-induced NFB activation.
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B activation, we performed EMSA. The results show that 1 nM TPA activated NFB (Fig. 4B
, Lane 1) and that pretreatment with 10 nM DHT decreased the amount of binding activity (Fig. 4B
, Lane 2). Expression of the IB- protein has been used as a marker for the activity of NFB. Therefore, we performed Western blot analyses on protein extracts from treated LNCaP cells to determine the levels of IB- under various treatment conditions, as shown in Fig. 4C
. Treatment with 10 nM DHT alone caused an increase in the expression of IB- protein, suggesting that AR might play a role in regulating IB- expression (Fig. 4C
, Lane 2). IB- protein expression decreased after 1 nM TPA treatment (Fig. 4C
, Lane 3) and was restored when the cells were pretreated with 10 nM DHT (Fig. 4C
, Lane 4). Western blot analyses of AR expression shows that DHT treatment increases AR protein expression (Fig. 4C
, Lanes 2 and 4) and that TPA treatment alone had no effect on the AR level (Fig. 4C
, Lane 3). Taken together, these results suggest that androgen suppresses NFB activity (Fig. 4, B
, Lane 2, and C, Lanes 2 and 4).
Ectopic Expression of RelA Protects LNCaP Cells from Androgen/AR and TPA-induced Apoptosis.
To investigate further the role of NFB in DHT/TPA-induced apoptosis, we hypothesized that overexpression of NFB would protect cells from apoptosis induced by DHT/TPA treatment. LNCaP cells were transfected with the pCDNA3 vector or with pCDNA3 containing the major activation subunit of NFB, known as RelA p65. Several independent transfected cell lines were established, and protein extracts from each were subjected to Western blot analyses with anti-p65 (RelA) antibody (Fig. 5A)
. The clonal line LNCaP-RelA (6)
was chosen for additional analysis.
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. These results indicate that overexpression of RelA protects cells from apoptosis induced by the combination of DHT and TPA.
Induction of Apoptosis by Androgen/AR and TPA Is Mediated by JNK Activity.
Reports have shown that when cells undergo apoptosis, JNK activity is increased (24
, 25)
, and recent studies have demonstrated that cross-talk exists between the JNK and NFB signaling pathways (25
, 26)
. It has also been proposed that JNK activity is an upstream event relative to the activation of caspase cascades during apoptosis. Because of the relationship between JNK and NFB, we tested whether the combination of DHT and TPA has an effect on JNK activation in LNCaP cells. The p38/JNK inhibitor SB202190 blocks both p38 and JNK activation (26)
. SB202190 was used to determine the effect of 10 nM DHT treatment, followed by 1 nM TPA, on JNK activity. Fig. 6, A and B
, shows the suppressive effect of SB202190 on TPA-induced apoptosis after DHT pretreatment. Inhibition of p38/JNK by SB202190 results in a >50% decrease in the induction of apoptosis as shown by TUNEL assay (Fig. 6B)
. These experiments suggest that induction of apoptosis in LNCaP cells by DHT/TPA is mediated through JNK activity. Western blot analyses of protein extracts, using an antibody for the activated (phosphorylated) form of JNK, show an increase in the detectable level of activated JNK in treated LNCaP cells (Fig. 6C
, Lane 4) but not in LNCaP-RelA cells (Fig. 6C
, Lane 8), suggesting that NFB may be able to suppress JNK activity.
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B activity, we used inhibitors of NFB. Fig. 7A
shows the effect of NFB inhibitors on NFB Luc activity in a transactivation assay. The NFB inhibitor parthenolide inhibited NFB activity in a dose-dependent manner (Fig. 7A
, Lanes 4 and 6). As a negative control, we also used a transfected mutant form of IB- (mIB-), which cannot be phosphorylated by IKK, to inhibit NFB activity, as shown in Fig. 7A
, Lane 8. To show the effect of NFB on inhibition of JNK activity, LNCaP cells were transfected with pCMX-mIk-B and treated with 1 nM TPA for 24 h (Fig. 7B
, Lanes 2, 4, and 6). Western blot analyses were performed using an antibody for phosphorylated JNK. Levels of phosphorylated JNK were increased in cells transfected with mIkB- (Fig. 7B
, Lane 2) or in cells treated with parthenolide (Fig. 7B
, Lane 4). These data suggest that an increase in JNK activity is linked to suppression of NFB.
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B seems inconsistent with data showing that treatment of LNCaP cells with TPA for 24 h results in the induction of both NFB (Fig. 4, A and B)
and JNK activity (Fig. 6)
. To clarify the role of NFB in regulating JNK activity, we determined the activity of JNK over 72 h after treatment with TPA. LNCaP cells were treated with TPA, and the level of phosphorylated c-jun (a JNK substrate) was determined at 24, 48, and 72 h. By 48 h, the level of c-jun phosphorylation declined to basal levels, as shown in Fig. 7C
. In another experiment, we determined the levels of activated c-JNK both in the presence and absence of an inhibitor of NFB. As shown in Fig. 7D
, Lane 2, the activity of JNK was elevated at 24 h but had declined to basal levels at 48 h. In the presence of the NFB inhibitor parthenolide, JNK activity remained elevated at 48 h, showing that the decline in JNK activity is associated with the activity of NFB.
Overall, our study presents data indicating that androgen/AR facilities TPA-induced apoptosis by interruption of NFB signaling, which leads to activation of JNK and subsequent induction of caspase-3-dependent signaling. Fig. 8
summarizes the TPA/JNK/caspase-3 signaling pathway that leads to apoptosis in androgen-sensitive LNCaP prostate cancer cells.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A potential AR target is the inducible transcription factor NFB (11)
. It has been shown that the activity of NFB is elevated in androgen-independent prostate cancer cell lines PC-3 and DU145 compared with the androgen-sensitive prostate cancer LNCaP cell line (31
, 32)
, suggesting that AR may suppress NFB activity. AR-mediated suppression of NFB could occur through several mechanisms. Cross-modulation, transcriptional interference, and physical interaction between AR and NFB have been shown (20
, 21)
. A direct interaction between AR and NFB/RelA (data not shown) (21)
might prevent RelA (p65) from binding to NFB binding sites or affect the ability of RelA to translocate to the nucleus after activating NFB. Increased expression of IB induced by DHT (Fig. 4C)
could be caused by the stabilization of IB protein or increased mRNA levels. Furthermore, pretreatment with 10 nM DHT, followed by 1 nM TPA, abrogated the TPA-mediated suppression of IB (Fig. 4C
, Lane 4 versus Lane 3), thus correlating with the ability of DHT to sensitize the cell to the proapoptotic influence of 1 nM TPA.
We have shown that the combination of TPA/DHT was unable to induce apoptosis in the LNCaP cell line overexpressing Rel A (LNCaP-Rel A; Fig. 5C
). NFB normally protects cells from induction of apoptosis by inhibition of signaling through the JNK pathway (9)
. We show that the combination of DHT/TPA activates the JNK pathway and that the normal protective effect of NFB is suppressed by the actions of androgen/AR in LNCaP cells. In contrast, JNK activity was abrogated in the LNCaP-RelA cells (Fig. 6C)
.
Our data show the role of androgen/AR in modulating the induction of apoptosis in LNCaP cells, using low doses of TPA and pretreatment with DHT. This suggests that combining DHT and TPA might result in a more effective proapoptotic response than treatment with androgen alone, particularly in the context of intermittent androgen therapy. The effect of androgen in facilitating low-dose TPA induction of apoptosis was inhibited by the antiandrogen bicalutamide (Casodex, 1 µM), a JNK inhibitor, and by overexpression of NFB. Taken together, our results indicate that in androgen-sensitive prostate cancer cells such as LNCaP, androgen/AR facilitates TPA-induced apoptosis by interruption of NFB signaling, which allows JNK activation to initiate the apoptotic caspase cascade through caspase-3. A key finding of our study is that androgen enables low concentrations of TPA (1 nM) to induce apoptosis.
Therapeutic approaches to selectively induce apoptosis by manipulating apoptotic pathways are being explored in a variety of clinical circumstances, and such approaches have been suggested as possible strategies to enhance intermittent androgen therapy in the treatment of prostate cancer (3 , 6) . The apoptotic process is subject to input from many different cell-signaling pathways. Understanding these pathways and their interactions is critical for effective integration of accumulating apoptosis-related information into therapeutic strategies. Here, we show that pretreatment with androgen facilitates induction of apoptosis with low concentrations of TPA. It may be possible that the effects of intermittent androgen therapy could be improved by agents that augment apoptosis (3 , 5 , 6 , 39 , 40) . The observations described here suggest a mechanism whereby androgen influences the apoptotic propensity of tumor cells.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Supported by NIH Grants CA55639, CA71870, and DK60912.
1 To whom requests for reprints should be addressed, at Department of Pathology, University of Rochester Medical Center, Box 626, 601 Elmwood Avenue, Rochester, NY 14642. E-mail: chang{at}urmc.rochester.edu 
2 The abbreviations used are: AR, androgen receptor; PKC, protein kinase C; TPA, 12-O-tetradecanoylphorbol acetate; NFB, nuclear factor B; TNF, tumor necrosis factor; IKK, IB kinase; JNK, c-Jun N-terminal kinase; DHT, 5--dihydrotestosterone; TUNEL, terminal transferase-mediated dUTP-biotin nick end-labeling; Luc, luciferase; EMSA, electromobility gel shift assay.
3 S. Altuwaijri, unpublished results.
Received 4/ 2/03. Revised 8/ 6/03. Accepted 8/27/03.
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