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. 2018 Oct;16(4):3211-3219.
doi: 10.3892/etm.2018.6538. Epub 2018 Jul 30.

Regulation of mPGES-1 composition and cell growth via the MAPK signaling pathway in jurkat cells

Yi-Qing Li  1   2 , Jiao-Ting Chen  1   2   3 , Song-Mei Yin  1 , Da-Nian Nie  1 , Zhi-Yuan He  1 , Shuang-Feng Xie  1 , Xiu-Ju Wang  1 , Yu-Dan Wu  1 , Jie Xiao  1 , Hong-Yun Liu  1 , Jie-Yu Wang  1 , Wen-Juan Yang  1 , Li-Ping Ma  1
Affiliations

Regulation of mPGES-1 composition and cell growth via the MAPK signaling pathway in jurkat cells

Yi-Qing Li et al. Exp Ther Med. 2018 Oct.

Abstract

Previous studies have suggested that microsomal prostaglandin E synthase-1 (mPGES-1) is highly expressed and closely associated with mitogen-activated protein kinase (MAPK) signaling pathways in various types of malignant cells. However, their expression patterns and function with respect to T-cell acute lymphoblastic leukemia (T-ALL) remain largely unknown. The present study investigated whether mPGES-1 served a crucial role in T-ALL and aimed to identify interactions between mPGES-1 and the MAPK signaling pathway in T-ALL. The results indicated that mPGES-1 overexpression in T-ALL jurkat cells was significantly decreased by RNA silencing. Decreasing mPGES-1 on a consistent basis may inhibit cell proliferation, induce apoptosis and arrest the cell cycle in T-ALL jurkat cells. Microarray and western blot analyses revealed that c-Jun N-terminal kinase served a role in the mPGES-1/prostaglandin E2/EP4/MAPK positive feedback loops. In addition, P38 and extracellular signal-regulated kinase 1/2 exhibited negative feedback effects on mPGES-1. In conclusion, the results suggested that cross-talk between mPGES-1 and the MAPK signaling pathway was very complex. Therefore, the combined regulation of mPGES-1 and the MAPK signaling pathway may be developed into a new candidate therapy for T-ALL in the future.

Keywords: T-cell acute lymphoblastic leukemia; feedback; jurkat cell; microsomal prostaglandin-E synthase; mitogen activated protein Kinase Signaling System.

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Figures

Figure 1.
Figure 1.
Lentiviral interference efficiency. Western blot analysis of the mPGES-1 protein expression in jurkat cells following lentiviral infection. *P<0.05 vs. jurkat group. mPGES-1, microsomal prostaglandin E synthase-1; NC, negative control; mPGES-1, microsomal prostaglandin E synthase-1.
Figure 2.
Figure 2.
Lentiviral infection efficiency. (A) Representative images of jurkat cells following lentiviral infection. (B) Flow cytometry analysis of the lentiviral infection efficiency of jurkat cells. NC, negative control; GFP, green fluorescent protein; CON, control; KD, jurkat cells transfected with shRNA (27743–1).
Figure 3.
Figure 3.
Effect of mPGES-1 silencing on the proliferation of jurkat cells. The proliferation of jurkat cells was observed at 24, 48 and 72 h following lentiviral infection; this was measured by a cell counting kit-8 assay. *P<0.05 vs. CON; #P<0.05 vs. NC. mPGES-1, microsomal prostaglandin E synthase-1; CON, control; KD, jurkat cells transfected with shRNA (27743–1); NC, negative control.
Figure 4.
Figure 4.
Effect of mPGES-1 silencing on the apoptosis and cell cycle of jurkat cells. (A) Cell apoptosis and (B) cell cycle distribution in jurkat cells following lentiviral infection, as determined by flow cytometry. *P<0.05 vs. CON; #P<0.05 vs. NC. mPGES-1, microsomal prostaglandin E synthase-1; CON, control; KD, jurkat cells transfected with shRNA (27743–1); NC, negative control; FITC, fluorescein isothiocyanate.
Figure 5.
Figure 5.
Effect of mPGES-1 silencing on signaling pathways. (A) Signaling pathway histogram revealed the enrichment of differential genes in classic pathways. Orange histogram represents a pathway, which is activated; blue histogram represents a pathway, which is inhibited. The ratio represents (number of genes changed significantly in the pathway)/(number of all genes in the pathway). (B) Heat map of gene expression values involved in the MAPK signaling pathway. mPGES-1, microsomal prostaglandin E synthase-1; MAPK, mitogen-activated protein kinase; KD, jurkat cells transfected with shRNA (27743–1); NC, negative control.
Figure 6.
Figure 6.
Effect of mPGES-1 silencing on MAPKs. Knockdown mPGES-1 significantly increased the phosphorylation of P38 and ERK1/2, while it decreased the phosphorylation level of JNK. *P<0.05. mPGES-1, microsomal prostaglandin E synthase-1; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal regulated kinase; JNK, c-Jun N-terminal kinase; KD, jurkat cells transfected with shRNA (27743–1); NC, negative control.
Figure 7.
Figure 7.
Effect of the EP4 receptor antagonist on MAPKs. Pre-incubating jurkat cells with the EP4 receptor antagonist L-161982 (20 µmol/l) for 24 h increased the phosphorylation of P38 and ERK1/2, while it decreased the phosphorylation of JNK. *P<0.05. MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal regulated kinase; JNK, c-Jun N-terminal kinase; KD, jurkat cells transfected with shRNA (27743–1); NC, negative control.
Figure 8.
Figure 8.
Effect of pre-incubating jurkat cells with MAPKs inhibitors on the expression of EGR-1 and mPGES-1. (A) Pre-incubated jurkat cells with MEK1/2 inhibitor U0126 (5 µmol/l; for 2 h) affected protein expression of EGR-1 and mPGES-1. (B) Pre-incubated jurkat cells with JNK inhibitor SP600125 (10 µmol/l; for 2 h) affected protein expression of EGR-1 and mPGES-1. (C) Pre-incubated jurkat cells with P38 inhibitor SB203580 (10 µmol/l; for 2 h) affected protein expression of EGR-1, but not mPGES-1. *P<0.05. mPGES-1, microsomal prostaglandin E synthase-1; MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal regulated kinase; JNK, c-Jun N-terminal kinase; EGR-1, early growth response protein-1.
Figure 9.
Figure 9.
Model of the proposed association between mPGES-1 and MAPKs in jurkat cells. MAPK, mitogen-activated protein kinase; ERK1/2, extracellular signal regulated kinase; JNK, c-Jun N-terminal kinase; EGR-1, early growth response protein-1; PGE2, prostaglandin E2; PGH2, prostaglandin H2.
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