Regulation of mPGES‑1 composition and cell growth via the MAPK signaling pathway in jurkat cells
- Authors:
- Published online on: July 30, 2018 https://doi.org/10.3892/etm.2018.6538
- Pages: 3211-3219
Abstract
Introduction
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, which accounts for 25% of adult ALL cases (1). Although the clinical outcome has been dramatically improved by a combination of chemotherapy and hematopoietic stem cell transplantation, the prognosis of T-ALL remains poor due to a high frequency of induction failure and early relapse. Therefore, continued studies to identify innovative modes of action in T-ALL and the development of specific targeting therapies are still urgently required (2).
The effect of prostaglandin E2 (PGE2) on cell growth has attracted attention in recent years. Previous studies have demonstrated that the secretion of PGE2 in endometrial cancer, colon cancer, colorectal cancer, ovarian cancer and other malignant cells is significantly increased (3,4), indicating that PGE2 is implicated in the occurrence and progression of cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal synthase responsible for converting COX-derived PGH2 into PGE2 (5). Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the synthesis of PGE2 by inhibiting COX and affecting various biological functions of tumors (6–8). However, due to the gastrointestinal and cardiovascular side effects of NSAIDs, their clinical application has been limited (9,10). In recent years, overexpression of mPGES-1 was observed in a number of solid tumors (11–13). A preliminary study by the authors confirmed for the first time that mPGES-1 is highly expressed in human acute myeloid leukemia (AML) primary cells and AML cell lines such as HL-60. Inhibiting mPGES-1/PGE2 may induce apoptosis, inhibit proliferation, arrest the cell cycle and improve chemosensitivity (14–16); however, the roles of mPGES-1/PGE2 in T-ALL cells are largely unknown.
Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK) and P38 subtypes, are a highly-conserved family of serine/threonine kinases that serve an important role in regulating cell growth, differentiation, inflammatory reactions and cancer progression (17,18). Previous studies have revealed that different MAPKs may be involved in the regulation of mPGES-1 expression induced by inflammatory stimuli (19–21). Interestingly, certain previous studies have hypothesized that the MAPK signaling pathway resides upstream of PGE2 and regulates the synthesis of PGE2 through early growth response protein-1 (EGR-1) (19), while in other contexts, it is located downstream of mPGES-1/PGE2 (20,21). The MAPK signaling pathway, once activated, may be further regulated by complex feedback loops exerting either positive or negative effects on cascade components (22). The present study aimed to investigate the effects of mPGES-1 on T-ALL jurkat cells in vitro and attempted to determine the interaction between mPGES-1 and MAPKs in jurkat cells.
Materials and methods
Materials
Human T-ALL jurkat cell line was obtained from the Hematology Research Institute (Tianjin, China). The EP4 receptor antagonist L-161982 was purchased from Cayman Chemical Company (Ann Arbor, MI, USA). The MEK1/2 inhibitor U0126, JNK inhibitor SP600125 and the P38 inhibitor SB203580 were purchased from Selleck Chemicals (Shanghai, China). The anti-ERK1/2 (cat. no. 9926; dilution, 1:1,000), anti-p-ERK1/2 (Thr202/Tyr204; cat. no. 9910; dilution, 1:2,000), anti-P38 (cat. no. 9926; dilution, 1:1,000), anti-p-P38 (Thr180/Tyr182; cat. no. 9910; dilution, 1:1,000), anti-JNK (cat. no. 9926; dilution, 1:1,000), anti-p-JNK (Thr183/Tyr185; cat. no. 9910; dilution, 1:1,000), anti-EGR-1 (cat. no. 4153; dilution, 1:1,000), anti-GAPDH (cat. no. 2118; dilution, 1:1,000) and anti-rabbit IgG, horseradish peroxidase-conjugated (cat. no. 7074; dilution, 1:2,000) antibodies were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA) and anti-mPGES-1 antibody (cat. no. 10004350; dilution, 1:1,000) was purchased from the Cayman Chemical Company.
Cell culture
Jurkat cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum (both Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA) at 37°C in 5% CO2. To test the effect of EP4 receptor, jurkat cells (8×105/well) were plated in 6-well plate and incubated with antagonist L-161982 (10 mM stock solution in dimethyl sulfoxide, further dissolved with RPMI 1640 to give a 33.3 µM working solution) for 24 h at 37°C in 5% CO2.
Lentivirus infection
Gene knockdown was performed using lentivirus short hairpin RNA (shRNA), which was synthesized by GeneChem Co., Ltd., (Shanghai, China). The shRNA was cloned into pLKO.1 (GV115) lentiviral vectors (hU6-MCS-CMV-EGFP, GeneChem Co., Ltd., Shanghai, China) at 40 nmol/l. Four shRNA-mPGES-1 targeting sequences (27740-1, 5′-GGGCTTCGTCTACTCCTTT-3′; 27741-1, 5′-TGCTGGTCATCAAGATGTA-3′; 27742-1, 5′-GGCTAAGAATGCAGACTTT-3′ and 27743-1, 5′-TTTCTGGTCCCTTCAGTAT-3′) were designed. The shRNA-negative control (NC) targeting sequence was 5′-TTCTCCGAACGTGTCACGT-3′. The culture containing lentivirus was added to the jurkat cells in the presence of 5 µg/ml polybrene (Shanghai GeneChem Co., Ltd.). Positively transfected cells were selected by 1 µg/ml puromycin after 24 h incubation at 37°C in 5% CO2. Stable cell lines were verified by western blot analysis as described below.
Cell proliferation assay
Cell proliferation was measured using a Cell Counting kit-8 (Dojindo Molecular Technologies, Inc., Kumamoto, Japan) in vitro. A total of 1×104 cells were plated per well in 96-well plates and incubated at 37°C with 5% CO2 for 24, 48 and 72 h. The cells were divided into three groups: i) KD group, jurkat cells transfected with shRNA (27743–1) targeting mPGES-1; ii) NC group, jurkat cells transfected with NC shRNA; and iii) Control (CON) group, jurkat cells without any treatment. A total of 10 µl CCK-8 was added to each well and the samples were incubated for a further 4 h. The optical density (OD) values were measured using a microplate reader (Bio-Rad Laboratories, Inc., Hercules, CA, USA) at 450 nm.
Flow cytometry
Following incubation in a serum-free RPMI 1640 medium overnight, jurkat cells were collected (115 × g, 5 min, room temperature) and rinsed twice with PBS. For cell cycle analysis, a total of 5×105 cells were fixed with 70% pre-chilled ethanol overnight at 4°C and stained with propidium iodide for 10 min at room temperature. The DNA content was analyzed by a BD FACStar flow cytometer (BD Biosciences, Franklin Lakes, NJ, USA). A total of 1×106 cells were washed and re-suspended in binding buffer and subsequently incubated with 5 ml Annexin V-fluorescein isothiocyanate (PE Annexin V Apoptosis Detection kit 1; BD Biosciences) for 15 min at room temperature in the dark. A total of 2.5 ml allophycocyanin (BD Biosciences) was added and the cells were analyzed with a FACScan flow cytometer (FACSCalibur; BD Biosciences). Fluorophores were excited at 640 nm. Data acquisition and analysis were performed using CellQuest software (v6.1×; BD Biosciences).
GeneChip assay
GeneChip assays were performed by Shanghai GeneChem Co., Ltd. (Shanghai, China). General steps were as follows: Total RNA was extracted using TRIzol reagent (Takara Bio, Inc., Otsu, Japan) according to the manufacturer protocol. The quantity and quality of the RNA were determined by spectrophotometer and 1% formaldehyde denaturing gel electrophoresis. An Affymetrix Gene Chip® Prime View™ Human Gene Expression array was used for the microarray analysis. Hybridization, data capture and analysis were performed by Shanghai GeneChem Co., Ltd. (Shanghai, China). Briefly, 100 ng total RNA was used for cDNA synthesis and biotin-tagged cRNA was produced by the Gene Chip IVT Labeling kit (Affymetrix; Thermo Fisher Scientific, Inc.). A total of 15 µg fragmented cRNA, with the controls oligo B2 and eukaryotic hybridization, were hybridized to each GeneChip array at 45°C for 16 h (Affymetrix Gene Chip Hybridization Oven 640) according to the manufacturer protocol. Following hybridization, the Gene Chip arrays were washed three times at room temperature and stained with streptavidin phycoerythrin onan (3×; 35°C; 300 sec) with Affymetrix Fluidics Station 450 followed by scanning with the Affymetrix Gene Chip Scanner 30007G. Molecular function and signaling pathways were analyzed using Gene Ontology (GO; http://www.geneontology.org/) and Kyoto Encyclopedia of Genes and Genomes (KEGG; http://www.kegg.jp/kegg/kegg4.html), respectively.
Western blot analysis
Cells were lysed with an appropriate volume of the radioimmunoprecipitation buffer (CWBIO; Biotechnology Co., Ltd., Beijing, China) supplemented with protease inhibitor cocktail (CWBIO; Biotechnology Co., Ltd., Beijing, China) and the protein concentrations were determined by bicinchoninic acid assays with bovine serum albumin (BSA; CWBIO, Biotechnology Co., Ltd., Beijing, China) as the standard. A total of 30 ng/20 µl protein was separated by 10% SDS-PAGE and transferred to polyvinylidene difluoride membranes (EMD Millipore, Billerica, MA, USA). Following blocking with Tris-buffered saline (TBS) containing 5% BSA diluted in TBS with Tween-20 for 1 h, the membranes were incubated overnight at 4°C with primary antibodies diluted according to the instruction followed by incubation with the horseradish peroxidase-conjugated secondary antibodies for 1 h at room temperature. The immunoreactive bands were detected using a chemiluminescent system (Thermo Fisher Scientific, Inc.) and quantified using ImageJ 1.43 (National Institutes of Health, Bethesda, MD, USA).
Statistical analysis
All experiments were performed three times. Data were processed using SPSS 20.0 software (IBM Corp., Armonk, NY, USA) and presented as the mean ± standard deviation. Statistical analysis was conducted using one-way analysis of variance followed by Student-Newman-Keuls post-hoc tests. P<0.05 was considered to indicate a statistically significant difference.
Results
The results of gene silencing by RNA interference
To establish a useful cell line, the expression of mPGES-1 was decreased via lentivirus shRNA interference. Following western blot analysis of the results, sequence 27743-1 was selected for use in the following experiments (as the KD group) as it displayed the highest interference rate when transfected into jurkat cells (P<0.05; Fig. 1). An inverted fluorescence microscope was used to observe the cells; it revealed that the KD and NC groups had a similar morphology to the CON group (Fig. 2A), indicating that the lentivirus infection had no notable effects on cell morphology. Subsequently, flow cytometry was utilized to detect the infection efficiency. The results revealed that the infection efficiency of the KD and NC groups were 84.87 and 83.17%, respectively (P<0.05; Fig. 2B). Infection efficiency allowed for cells to be used in further experiment.
mPGES-1 silencing inhibits proliferation, induces apoptosis and arrests the cell cycle in jurkat cells
To evaluate the effect of mPGES-1 on the proliferation of jurkat cells, a CCK-8 experiment was conducted. The results revealed that the proliferation of the KD group was significantly slower compared with the NC and CON groups at 24, 48 and 72 h (P<0.05), whereas no significant difference was observed between the NC group and the CON group at any time point (Fig. 3). In addition, the percentage of total apoptotic cells (total Annexin-V-FITC+ cells) was significantly increased in the KD group compared with the CON and NC groups when assayed by flow cytometry (P<0.05; Fig. 4A). The populations of early (Annexin-V-FITC+, PI-cells) and late apoptotic cells (Annexin-V-FITC+, PI+ cells) were also significantly increased in the KD group compared with the NC and CON groups (P<0.05; Fig. 4A). Silencing mPGES-1 may also influence the cell cycle of jurkat cells. The percentage of cells in the G1 phase was significantly increased, while the percentage at the S phase was significantly reduced in the KD group compared with the NC and CON groups (P<0.05; Fig. 4B). These results indicated that decreasing mPGES-1 inhibited proliferation, induced apoptosis and arrested the cell cycle the G1 phase in jurkat cells.
Reducing the expression of mPGES-1 inhibits the MAPK signaling pathway
To further understand the mechanism of mPGES-1's effects on jurkat cells, microarray analysis was used to detect the changes in gene expression following knockdown of mPGS-1. It was revealed that 456 genes had changed significantly following the knockdown of mPGES-1. These genes primarily participated in cell proliferation, apoptosis, protein metabolism and immune response as indicated by GO analysis (data not shown). The associated signaling pathways were analyzed via KEGG software and the results indicated that MAPK had the clearest change in all relevant signaling pathways. The MAPK signaling pathway was significantly inhibited (P=6.78×10−4) following knockdown of mPGES-1 (Fig. 5A). A total of 12 genes in the MAPK signaling pathway, including ARRB2, FOS, PPP3CB, FGFR3, MAP3K8, ZAK, CACNA1A, PRKACB, IL1R2, RAC1, DUSP2 and NR4A1 were involved (Fig. 5B and Table I). These findings revealed that the biological function of jurkat cells may be associated with the MAPK signaling pathway, and that mPGES-1 may be located upstream of it.
The MAPK signaling pathway is one of the most important signal transduction systems. It participates in cell growth, development, differentiation, and other physiological and pathological processes (23). Previous studies have demonstrated that the major MAPK signaling pathway subfamilies associated with COX-2/mPGES-1 or lipopolysaccharide-activated inflammatory responses may be ERK1/2, JNK and P38 (23). There is cross-talk between these three components, which leads to either coordination or inhibition (24). To identify which signaling pathway is associated with the function of mPGES-1 in jurkat cells, the phosphorylation status of major MAPK subfamilies was investigated following mPGES-1 silencing. The expression levels of phosphorylated (p)-P38 and p-ERK1/2 were significantly increased, while p-JNK was significantly decreased compared with the NC group (P<0.05; Fig. 6). Based on these results, the authors speculated that mPGES-1 may affect the growth of jurkat cells through the JNK/MAPK signaling pathway. Alternatively, decreasing mPGES-1 may activate the P38 MAPK and ERK1/2/MAPK signaling pathways. Whether the subfamilies are regulated independently or as a result of cross-talk is a question, which requires further investigation.
EP4 receptor mediates the regulation of mPGES-1 on the MAPK signaling pathway
PGE2 has diverse actions and stimulates key downstream signal transduction pathways by binding to its prostanoid receptors (EP1, EP2, EP3 and EP4) (25). Binding of PGE2 to different receptors may lead to the activation of different signaling pathways (25). A previous study by the authors reported that mPGES-1/PGE2 was closely associated with MAPKs, however, which subtype of prostanoid receptors mediated the activation of MAPKs remained unknown. In the present study jurkat cells were pre-incubated with EP4 receptor antagonist L-161982 and then the phosphorylation of MAPKs was examined. It was observed that the changes in the MAPKs were consistent with the results obtained following silencing of mPGES-1 (P<0.05; Fig. 7). This may indicate that mPGES-1/PGE2 regulates MAPKs by combining with the EP4 receptor.
MAPKs feedback on mPGES-1 may be partly via EGR-1
Several previous studies seem to indicate that MAPKs regulate mPGES-1 via EGR-1, a transcription factor that regulates the composition of mPGES-1 (26–29). The authors hypothesized that MAPKs may regulate the expression of mPGES-1 by regulating EGR-1 in jurkat cells. To confirm this hypothesis, the jurkat cells were treated with inhibitors U0126, SB203580 and SP600125 against the phosphorylation of ERK1/2, P38 and JNK, respectively. It was revealed that following the inhibition of the ERK1/2/MAPK signaling pathway, the expression of mPGES-1 and EGR-1 was significantly reduced (P<0.05; Fig. 8A), while the JNK and P38 inhibitors reduced the changes observed in EGR-1 and mPGES-1 (Fig. 8B and C). These results suggest that the ERK1/2/MAPK signaling pathway may regulate the expression of mPGES-1 through EGR-1.
Discussion
In the present study, the functional role of mPGES-1 silencing was elucidated in the proliferation, apoptosis and cell cycle of jurkat cells. Since it was first raised as a promising therapeutic target in 1999 (30), studies have revealed that prolonged and excessive production of mPGES-1 can alter a number of biological processes, leading to intractable pathologies, including inflammation and cancer (11–13). Therefore, blocking the expression of mPGES-1 is often an important strategy in treating these conditions. Previous studies by the authors have confirmed that mPGES-1 is expressed highly in a variety of leukemia cells, including HL-60 (16), K562, jurkat and Raji (unpublished data). In the present study, it was revealed that decreasing mPGES-1 affected the growth of T-ALL jurkat cells and was also associated with the MAPK signaling pathway. As only one cell line was used in the experiments, it is not clear if such phenomenon exists in other T-ALL cell lines or primary cells; the authors believe that this is intriguing and worth exploring in future studies.
The roles of MAPKs in T-ALL have been previously described (31–33). The major MAPK signaling pathway subfamilies, including ERK1/2, JNK and P38 serve key roles in the regulation of the expression of various inflammatory genes, such as mPGES-1 (23). Based on these previous results, it was speculated that MAPKs may be involved in the regulation of mPGES-1 in T-ALL. Using microarray and western blot analysis, it was confirmed that mPGES-1 may affect the growth of jurkat cells via MAPKs. Interestingly, the effects of mPGES-1 on MAPK subfamilies were completely different. The JNK/MAPK signaling pathway was activated in the NC group, whereas this activation was inhibited in the KD group. However, the other two subfamilies, ERK1/2 and P38, displayed the opposite response following knockdown mPGES-1. These results indicated that mPGES-1 is located upstream of MAPKs, that MAPKs may be involved in the impact of mPGES-1 on jurkat cells and that the three subfamilies of MAPKs had different responses to mPGES-1 and there may be cross-talk between them; however, the exact mechanism requires further investigation.
mPGES-1 affects the function of tumor cells by increasing PGE2 synthesis. PGE2 exerts its biological actions by binding to four specific receptor subtypes known as EP1, EP2, EP3 and EP4 (34). The EP receptors are involved in the generation and progression of tumors through the activation of different signaling pathways (35–37). Qian et al (38) reported that PGE2 stimulates human brain natriuretic peptide expression via the EP4-ERK1/2/MAPK signaling pathway. Mendez and LaPointe (39) also reported that PGE2 induces protein synthesis in cardiac myocytes, partly via activation of the EP4 receptor and subsequent activation of the ERK1/2/MAPK signaling pathway. In the present study the EP4 receptor was blocked by its antagonist, L-161982; this lead to a similar effect on MAPKs as those caused by mPGES-1 silencing. These results indicated that mPGES-1/PGE2 affected the growth of jurkat cells via EP4-dependent activation of the MAPK signaling pathway. However, the phosphorylated and activated subtype of MAPKs regulated by mPGES-1/PGE2/EP4 was different from that in Qian and Mendez's studies. This may be due to the different cell line used in the present experiment.
Accumulating evidence indicates that the activation of MAPKs is crucial for the expression of EGR-1 (40,41). EGR-1 is a zinc finger transcription factor, which binds to GC-rich sequences, such as mPGES-1, in the regulatory region of its target genes (42). In the present study, blocking the ERK1/2/MAPK pathway induced a decrease in EGR-1 and mPGES-1, so it was speculated that the ERK1/2/MAPK signaling pathway may regulate mPGES-1 expression through EGR-1 (Fig. 9). Blocking the P38/MAPK or JNK/MAPK pathways induced an increase in EGR-1, while it decreased mPGES-1. These results may indicate the possibility of other potential mechanism underlying the regulation of mPGES-1, in addition to EGR-1.
Based on the above findings, it is clear that mPGES-1 serves an important role in T-ALL jurkat cells by activating the JNK/MAPK signaling pathway, which in turn is required to achieve high levels of mPGES-1. This suggests that a positive feedback loop mediated by the JNK/MAPK signaling pathway promotes mPGES-1 induction. The results of the present study contradict the findings of a previous study, which mentioned a positive feedback loop between mPGES-1 and the ERK1/2/MAPK signaling pathway in macrophages (43). One potential explanation is that the present study performed experiments with all three of the classical subfamilies (ERK1/2/MAPK, JNK/MAPK and P38/MAPK) in jurkat cells, instead of macrophages. By exploring the growth of jurkat cells, it was observed that the effect of the positive feedback loop induced by the JNK/MAPK signaling pathway may be greater than that of the negative feedback induced by the ERK1/2/MAPK and P38/MAPK signaling pathways, subsequently leading to an inhibition of proliferation, induction of apoptosis and arrest of the cell cycle. However, the involvement of negative feedback loops may induce drug resistance or even treatment failure (44,45). The findings of the present study raised the possibility that combined treatments of mPGES-1 with ERK1/2 and P38 inhibitors may be a novel therapeutic strategy for T-ALL.
Acknowledgments
Not applicable.
Funding
The present study was supported by grants from the National Natural Science Foundation of China (grant no. 81200342), the Guangdong Science and Technology Department (grant nos. 2014A020212085 and 2016A020215062), the Natural Science Foundation of Guangdong Province (grant no. 2016A030313360), the State Scholarship Fund of China (grant no. CSC 201606380189), the Key Laboratory of Malignant Tumor Molecular Mechanism and the Translational Medicine of Guangzhou Bureau of Science and Information Technology [(grant no. 163 (2013)] and the Key Laboratory of Malignant Tumor Gene Regulation and the Target Therapy of Guangdong Higher Education Institutes (grant no. KLB09001).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
S-MY and D-NN designed the study, and analyzed and interpreted the data. Y-QL and J-TC conducted the experiments and contributed to writing the manuscript. All other authors, Z-YH, S-FX, X-JW, Y-DW, JX, H-YL, J-YW, W-JY and L-PM made substantial contributions to the experiments and the acquisition of data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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