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B Signaling Pathway
Division of Research, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia 30322
Address all correspondence and requests for reprints to: Neil Sidell, Ph.D., Department of Gynecology and Obstetrics, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, Georgia 30322. E-mail: nsidell{at}emory.edu.
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Abstract |
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B (NF-B) while having little effect on activating protein-1 (AP-1) binding. This effect on NF-B binding was blocked in the presence of the NF-B inhibitor, pyrrolidine dithiocarbamate (PDTC). The data also showed that the activity of RU486 on NF-B binding correlated with the ability of this compound to induce apoptosis of EM42 cells. To investigate a cause and effect relationship between these two phenomena, we evaluated the effects of RU486 treatment on the expression of two apoptosis-related genes, bax and bcl-2, known to be regulated through NF-B binding on their promoter. RT-PCR demonstrated that RU486 significantly induced bax mRNA levels, while suppressing mRNA of bcl-2. Alteration of these genes by RU486 was inhibited in the presence of 100 µM PDTC. Correspondingly, PDTC antagonized the ability of RU486 to inhibit the growth and induce apoptosis of EM42 cells. This study demonstrates that the inhibition of growth and apoptosis of human endometrial cells by RU486 involves stimulation of NF-B binding with subsequent modulation of apoptosis regulatory genes bax and bcl-2. |
Introduction |
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The decision of cells to undergo apoptosis is controlled by external signals in combination with an autonomous genetic program. Cell death is regulated at several intracellular checkpoints by the actions of different members of the bcl-2 gene family (5). The bcl-2 oncogene, which was first identified in human B cell tumors (6), protects against apoptosis and is the founding member of this family. Another member of the family is bax, which promotes apoptosis and encodes a protein that can form homodimers or heterodimers with bcl-2 (7). In human epithelial endometrial cells, bcl-2 predominates at the end of the follicular phase and is low or absent in the secretory phase, when electron microscopic analysis shows apoptotic cells (8). These studies suggested that bcl-2 might be involved in protection against apoptosis during the proliferative phase of the menstrual cycle.
The transcription factor NF-B site has been identified in the promoters of bcl-2 and bax as well as numerous other genes that play a role in cell growth regulation and proliferation (9). Reports indicate that activation of NF-B can induce apoptosis in some cells (10, 11), whereas inhibition of NF-B during the resolution of inflammation helps protract the inflammatory response and prevent apoptosis (12). This knowledge has prompted the present study to investigate the mechanism by which endometrial cell growth is inhibited by RU486. Our results demonstrate that RU486 rapidly induces apoptosis in human endometrial cells. This effect occurs via a NF-B-dependent mechanism and appears to involve the two apoptosis-regulating genes, bcl-2 and bax.
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Materials and Methods |
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The human endometrial epithelial cell line EM42 was established from benign proliferative endometrium from a patient undergoing hysterectomy for leiomyomata and was originally a gift from Dr. N. Desai (University MacDonald Women’s Hospital, Case Western Reserve University, Cleveland, OH) (13). Cells were grown in RPMI 1640 medium (Cellgro, Herndon, VA) supplemented with 10% heat-inactivated fetal bovine serum, HEPES buffer, 50 IU/ml penicillin/streptomycin, and 1 µg amphotericin (complete medium) as previously described (14). RU486 and phorbol 12-myristate 13-acetate (Sigma-Aldrich, St. Louis, MO) were dissolved in dimethylsulfoxide (0.2% of final volume). Pyrrolidine dithiocarbamate (PDTC; Sigma-Aldrich) was dissolved in PBS buffer solution. TACs Apoptotic DNA Laddering Kit was obtained from R\|[amp ]\|D Systems, Inc. (Minneapolis, MN). Poly(dI-dC) was purchased from Amersham Pharmacia Biotech (Piscataway, NJ); NF-B and activating protein-1 (AP-1) consensus oligonucleotides were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA); the 5' DNA Terminus Labeling System was purchased from Life Technologies, Inc. (Gaithersburg, MD); [
-32P]deoxy-ATP was purchased from PerkinElmer (Boston, MA). All RT-PCR kit components were obtained from PerkinElmer (PE Applied Biosystems, Foster City, CA). All other chemicals were purchased from Sigma-Aldrich unless otherwise indicated.
EMSA
Nuclear protein extracts from EM42 cells were prepared for EMSA as described previously (15). The protein content of the nuclear extract was determined using the bicinchoninic acid protein assay kit (Sigma-Aldrich) according to the manufacturer’s protocol. EMSA experiments were performed using double-stranded oligonucleotides comprising the consensus sequences (underlined) for NF-B (5'-AGTTGAGGGGACTTTCCCAGGC) and AP-1 (5'-GCTTGATGACTCAGCCGGAA). The binding site for AP-1 comprised the phorbol ester-responsive element. Oligonucleotides were end labeled with [-32P]deoxy-ATP using T4 polynucleotide kinase as recommended by the manufacturer. In the mutated NF-B oligonucleotide, the B motif was changed to GGcGACTTTCCC. For mutated AP-1 oligonucleotide, the B motif was changed to TGACTtg. Nuclear proteins (3 µg for NF-B, 5 µg for AP-1) from control and treated cells were incubated with the 32P-labeled oligonucleotide probe under binding conditions [10 mM HEPES (pH 7.9), Tris-HCl (pH 7.9), 50 mM KCl, 0.1 mM EDTA, 1 mM dithiothreitol, 12% (vol/vol) glycerol, and 2 µg poly(dI-dC)] for 20 min at room temperature in a final volume of 20 µl. For cold competition, a 100-fold excess of the respective unlabeled consensus oligonucleotides (AP-1 and NF-B) was added with the probe. The same amount of mutated oligonucleotides added with the probe was used as another control. All of these used the same binding conditions as described above. After binding, protein-DNA complexes were electrophoresed on a native 4.5% polyacrylamide gel at 120 V using 1x Tris-glycine buffer (10x Tris-glycine: 30.28 g Tris base, and 142.7 g glycine, 3.92 g EDTA, with H2O added up to 1 liter, pH 8.5). Each gel was then dried and subjected to autoradiography at -80 C for up to 72 h.
Cell growth
EM42 cells (3 x 105 cells/well) were seeded in six-well plates and incubated with vehicle control, 20 µM RU486, 100 µM PDTC, or 100 µM PDTC for 1 h, followed by 20 µM RU486, then treated for a total of 1–4 d. On d 1, 2, 3, and 4, the cells were harvested by trypsinization, and viable cells were counted using a hemocytometer by trypan blue exclusion.
Detection of DNA fragmentation
Internucleosomal degradation of genomic DNA due to activation of endogenous endonuclease is one feature that occurs during apoptosis. The release of oligonucleosome-associated DNA fragments in this process results in a DNA ladder when analyzed by agarose gel electrophoresis. Detecting internucleosomal DNA fragmentation and displaying DNA laddering using TACS Apoptotic DNA Laddering Kits (R\|[amp ]\|D Systems, Inc.) were used to evaluate apoptotic cell death. Procedures for DNA isolation and detection followed the protocol provided by the product supplier. After running it in a 1.5% TreviGel 500 gel (wt/vol) in 1x Tris-acetate, DNA was visualized with ethidium bromide staining under a UV transilluminator and photographed.
RT-PCR
Total RNA was prepared from cultured EM42 cells using TRIzol reagent (Life Technologies, Inc.). The sequences of PCR primers synthesized by Genosys (The Woodlands, TX) were: for bax: sense, 5'-CCAGCTCTGAACAGATCATG-3'; antisense, 5'-AGCTCCATATTGCTATCCAG-3'; for bcl-2: sense, 5'-CAATCAAAGCCAAGCAGA-3'; antisense, 5'-CCAAACATCCAGAGACAA-3'; for glyceraldehyde-3-phosphate-dehyrogenase (GAPDH): sense, 5'-CCATGGAGAAGGCTGGGG-3'; antisense, 5'-CAAAGTTGTCATGGATGACC-3', according to published data (14, 16). The RT-PCR was carried out as previously described (14). The samples were first denatured at 95 C for 30 sec, followed by 32 PCR cycles, each with temperature variations as follows: 95 C for 30 sec, 60 C for 30 sec, and 72 C for 1 min. The last cycle was followed by an additional extension incubation of 7 min at 72 C. Analysis of amplicons was visualized on 1% agarose gel containing 0.2 µg/µl ethidium bromide and were visualized under UV transilluminator. The densitometric analysis of PCR products was performed using the computer software (Quantity One, Bio-Rad Laboratories, Inc., Hercules, CA) and a GS-700 Imaging Densitometer (Bio-Rad Laboratories, Inc.), and was standardized by GAPDH. The ratio of bax or bcl-2/GAPDH product bands in the control group was considered 100%. Values for the treatment group bax or bcl-2/GAPDH ratio were given as a percentage of the control. A 100-bp ladder (Life Technologies, Inc.) was used as a size standard.
Statistical analysis
All experiments were repeated a minimum of three times. All gel-shift assays and RT-PCR data are expressed as the mean ± SE. The data in most figures are from a representative experiment, which was qualitatively similar in the replicate experiments. Statistical significance was determined by t test (two-tailed) comparison between two groups in a dataset. The asterisks shown in the figures indicate significant differences between experimental groups and the corresponding control condition (see figure legends).
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Results |
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B activation
Previous studies showed that RU486 could inhibit endometrial cell growth (2, 3). To elucidate the mechanism(s) responsible for the RU486 inhibition, we performed gel mobility shift assays to determine whether this inhibition might occur via NF-B- or/and AP-1-dependent mechanisms. As shown in Fig. 1
, culturing EM42 cells with 100 µM RU486 for 24 h caused a marked induction of NF-B binding compared with the control. We also evaluated for RU486 regulation of AP-1 binding activity. As shown in Fig. 2, 100 µM RU486 only slightly stimulated AP-1 binding compared with the control group. As a result of competition assays, specific bands for NF-B (Fig. 1, lane 2) and AP-1 (Fig. 2, lane 4) were attenuated by a 100-fold molar excess of unlabeled respective oligonucleotides. There were no specific bands when the NF-B (Fig. 1, lane 5) or AP-1 (data not shown) probes were mutagenized. These results all indicated that both bindings were specific.
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Previous reports have demonstrated that RU486 can induce apoptosis in various cell types and is considered to be mediated through several mechanisms (17, 18). Figure 3 shows that RU486 also induced apoptosis of EM42 endometrial cells; a distinct oligosomal ladder was observed 3 d after treatment with RU486 (100 µM). This effect was negligible in cells treated with vehicle (Fig. 3, lane 1).
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Having determined that RU486 treatment of EM42 cells induced NF-B-binding activity and apoptosis of the cells, we addressed the question of a possible link between these two phenomena. The NF-B signaling cascade is involved in the induction of apoptosis in a variety of circumstances through its regulation of the apoptosis-related genes, bcl-2 and bax (19). In many cells, bax promotes apoptosis by opposing the action of bcl-2 (20). Inhibition of NF-B has been shown to reduce bax expression in vivo (12). Thus, using RT-PCR, we assessed the ability of RU486 to alter bax and bcl-2 mRNA in EM42 cells. As shown in Fig. 4, culturing cells with 100 µM RU486 for 3 d significantly increased bax mRNA, whereas it down-regulated bcl-2 gene expression compared with the control.
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B activity suppresses RU486 effects on bax and bcl-2 gene expression
To establish a cause and effect relationship between RU486 induction of apoptosis and NF-B binding, we used PDTC as a general inhibitor of NF-B to prevent NF-B-mediated transcriptional activation (21). PDTC, at a concentration of 100 µM alone, decreased NF-B-binding activity, but had no significant effect on bax or bcl-2 gene expression. In contrast, pretreatment with this compound for 1 h, followed by treatment with RU486 for another 24 h, significantly blocked RU486 induction of NF-B binding compared with the control or PDTC alone (Fig. 5) and also significantly antagonized RU486 up-regulation of bax and down-regulation of bcl-2 gene expression (Fig. 6). These findings indicate that RU486-induced changes in bax and bcl-2 expression in EM42 endometrial cells are NF-B dependent and support the concept that activation of NF-B plays a necessary role in the clinical efficacy of RU486 in endometrial cell growth inhibition.
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B by PDTC suppresses RU486-induced growth inhibition and apoptosis of EM42 cells
To confirm that transcriptional activation by NF-B is directly involved in the cellular effects of RU486, we assessed whether treatment with PDTC also antagonized RU486-mediated growth inhibition and induction of apoptosis. Figure 7 shows that this was indeed the case; growth inhibition of EM42 cells by RU486 was partially reversed by pretreating the cells with PDTC for 1 h before adding RU486 for various time periods (Fig. 7A). After 4 d of RU486 treatment, there were very few viable cells remaining in the RU486 cultures, whereas the number of cells cultured with RU486 plus PDTC were approximately 60% of control value. Figure 7B demonstrates that PDTC also reduced the appearance of distinct DNA laddering caused by RU486, an indication that apop-tosis was also inhibited. PDTC alone showed little effect on cell growth or apoptosis.
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Discussion |
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NF-B, one of the early response transcription factors, has been shown to play a pivotal role in the regulation of genes that are involved in the cascade of events leading to cellular apoptosis (20, 26). Matsushita et al. (27) demonstrated that up-regulation of NF-B in endothelial cells stimulated apoptosis by 75%. Haddad and Land (19) found that a decrease in NF-B activity through stimulation of I-B expression inhibited apoptosis-related events in both human umbilical vein endothelial cells and calf pulmonary artery endothelial cells. In the present study we demonstrated that RU486 can markedly increase NF-B-binding activity in human endometrial cells, but has little effect on AP-1. Thus, although NF-B and AP-1 have shown synchronous regulation by a variety of hormone receptor agonists and antagonists (28) as well as antioxidants (29), it is apparent that they are differentially regulated by RU486. Our finding of a link between RU486 induction of apoptosis and the ability of this compound to up-regulate NF-B is consistent with studies demonstrating a similar link in human leukemic T cells (30).
In contrast to our results demonstrating up-regulation of NF-B binding by RU486 in EM42 endometrial cells, we showed in a previous study that RU486 could retard nuclear binding of NF-B induced by the linoleate oxidative product 13-hydroperoxide octadecadienoic acid (13-HPODE) in the mouse macrophage cell line RAW (31). Although the reason(s) for the opposite effects on NF-B activity of RU486 in EM42 vs. RAW cells is unknown, conflicting results have similarly been reported in disparate cells types with other agents. Thus, the natural peroxisome proliferator-activated receptor- (PPAR) agonist 15-deoxy-
12,14-prostaglandin J2 has been shown to induce binding of NF-B in activated human T lymphocytes (32), while markedly inhibiting NF-B activity in human monocytes (33). One reason for the cell type specificity in the effects of agents on NF-B could be that different signaling pathways may be evoked in the different cell systems. Thus, in the case of 15-deoxy-12,14-prostaglandin J2, while its inhibition of NF-B in monocytes has been shown to be mediated through PPAR (33), induction of NF-B in activated T cells does not occur through this signaling pathway (32). As 13-HPODE may also function as a PPAR ligand (34), inhibition of 13-HPODE-induced NF-B activity by RU486 in monocytes is likely to be PPAR dependent. On the other hand, there is no evidence of such dependence in the action of RU486 on NF-B in EM42 cells.
Cellular programming resulting in apoptosis involves several genes, including bcl-2 and bax. There are conflicting reports about the effects of RU486 on these two genes. Several studies (18, 35) indicated that RU486 down-regulated bcl-2 gene expression but had little effect on bax. In contrast, other reports have shown that RU486 can induce bcl-2 while showing no effect on bax expression (36). The fact that the upstream promoter region of these two genes contains NF-B-binding sites (37, 38) together with the suggested physiological roles of members of the bcl-2 gene family in regulating apoptosis of normal cycling endometrial cells (8) prompted us to investigate a possible association among RU486-induced regulation of apoptosis, NF-B, and bcl-2/bax expression in EM42 cells. The results showed that RU486 treatment significantly increased bax while reducing bcl-2 expression. The direction of both of these RU486-mediated changes is consistent with the well characterized roles of these genes in affecting apoptosis (39). We also determined that the specific NF-B inhibitor, PDTC, prevented RU486 up-regulation of bax and down-regulation of bcl-2 in these cells, and that growth inhibition and DNA fragmentation induced by RU486 treatment can be suppressed by cotreatment with PDTC. These findings confirm that the induction of NF-B binding by RU486 plays an essential role in regulating apoptosis-related events in EM42 cells. The down-regulation of bcl-2 expression resulting from RU486 induction of NF-B activity is surprising. For most genes, binding of NF-B proteins to promoter sites results in activation, rather than suppression, of transcription (40). However, conditions giving rise to negative regulation by NF-B have also been described. For example, Matsushita et al. (27) showed that activation of NF-B by hypoxia down-regulated bcl-2 expression in endothelial cells, with a resulting increase in apoptosis. In another study, it was shown that PDTC significantly attenuated the hypoxia-induced apoptosis of endothelial cells by blocking NF-B activation and down-regulation of bcl-2 (41). Similar protection against apoptosis by PDTC has been reported in colon cancer cells (42), although in various other cell systems blockade of NF-B by PDTC was demonstrated to induce apoptosis (43, 44). As such, the effects of increased NF-B binding by RU486 or other compounds on cell growth and viability are clearly cell type specific and may depend on the resultant effects of a variety of apoptosis-related genes whose expression is regulated by NF-B trans-activation as well as the quality of regulation (positive or negative) induced by NF-B on each individual gene.
Taken together, our study showed that the ability of RU486 to regulate endometrial cell growth is at least partially due to promotion of cellular apoptosis. This effect corresponds to a marked increase in NF-B-binding activity and subsequently to overexpression of bax and down-regulation of bcl-2. As RU486 or related compounds are being increasingly considered in the medical management of endometriosis, studies of its mechanism of action in the reproductive tract need to be aggressively pursued.
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Acknowledgments |
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Footnotes |
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Abbreviations: AP-1, Activating protein-1; GAPDH, glyceraldehyde-3-phosphate-dehyrogenase; 13-HPODE, 13-hydroperoxide octadecadienoic acid; NF-B, nuclear factor-B; PDTC, pyrrolidine dithiocarbamate; PPAR, peroxisome proliferator-activated receptor-.
Received June 4, 2002.
Accepted October 17, 2002.
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References |
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and TNF-related apoptosis-inducing ligand-induced apoptosis through an NF-B-dependent process. J Biol Chem 276:45548–45554B/IB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells. Cancer Res 60:4426–4432B in the resolution of inflammation. Nat Med 7:1291–1297[CrossRef][Medline]
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12,14-PGJ2 induces IL-8 production in human T cells by a mitogen-activated protein kinase pathway. J Immunol 168:1372–1379 (PPAR-) on the expression of inflammatory cytokines and apoptosis induction in rheumatoid synovial fibroblasts and monocytes. J Autoimmun 17:215–221[CrossRef][Medline]
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B activity. Cancer Lett 173:53–61[CrossRef][Medline]This article has been cited by other articles:
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