mPGES-1/PGE2 promotes the growth of T-ALL cells in vitro and in vivo by regulating the expression of MTDH via the EP3/cAMP/PKA/CREB pathway

Abstract

T-cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy that is characterized by a high frequency of induction failure and by early relapse. Many studies have revealed that metadherin (MTDH) is highly expressed in a variety of malignant solid tumours and plays an important role in the occurrence and development of tumours. However, the relationship between the expression of MTDH and T-ALL has not yet been reported, and the regulatory factors of MTDH are still unknown. Our previous studies found that mPGES-1/PGE2 was important for promoting the growth of leukaemia cells. In the present study, we found that MTDH was highly expressed in primary T-ALL cells and in the Jurkat cell line. Our results showed that mPGES-1/PGE2 regulates the expression of MTDH through the EP3/cAMP/PKA-CREB pathway in T-ALL cells. Downregulation of MTDH inhibits the growth of Jurkat cells in vitro and in vivo. Our results suggest that MTDH could be a potential target for the treatment of T-ALL.

Growth of T-cell lymphoma cells is inhibited by mPGES-1/PGE2 suppression via JAK/STAT, TGF-β/Smad3 and PI3K/AKT signal pathways

“…Firstly, only one inhibitor of mPGES1, CAY10526, was used. However, its efficacy and selectivity on mPGES1 has been confirmed (15)(16)(17) including in our previous report (7), and was even employed as reference compound (18). Experiments are currently undergoing including knock down of mPGES-1 by RNA silencing and exogenous PGE2 supplement for rescue.…”

“…Meanwhile, P38 and extracellular signal-regulated kinase 1/2 exerted negative feedback on mPGES-1 (5,30). More recently, we published that mPGES-1/PGE2 promoted proliferation of T-ALL cells by modulating MTDH via the EP3/cAMP/ PKA/CREB pathway (7). In addition, we have found high expression of COX-2/mPGES-1 predicted a poor prognosis of diffuse large B cell lymphoma and affected cell proliferation by interacting with NF-κB p65 (manuscript in submission).…”

“…As several studies have shown that CAY10526 is an isoformselective inhibitor of PGE2 production through the selective modulation of mPGES-1 expression (15)(16)(17), and was even selected as reference compound when newer compound was synthesized and tested (18). The dose of CAY10526 used in the studies ranged from 1.8 to 300 μM for different cells and experimental conditions, including our previous report showing CAY10526 [half inhibitory concentration (IC50): 16.7 μM at 24 h] reduced PGE2 synthesis in primary T-cell acute lymphoblastic leukemia (T-ALL) cells (7). Therefore, 10-80 μM of CAY10526 were used in the subsequent experiments.…”

“…Over-expression of mPGES-1 has been found in many types of solid tumors and hematologic malignancies (2)(3)(4). Our previous studies have shown that mPGES-1 was over-expressed in human leukemia primary cells and cell lines, and inhibiting mP-GES-1 could suppress proliferation, induce apoptosis and arrest the cell cycle of leukemia cells in vitro and in vivo (5)(6)(7). However, the role and mechanism of mPGES-1/ PGE2 in TCL has remained largely unknown.…”

Orchestral role of lipid metabolic reprogramming in T-cell malignancy

“…Lipids of eicosanoids have immunomodulatory consequences ( 177 ). The prostaglandin E2 promotes the tumor progression of T-acute lymphoblastic leukemia by affecting the cAMP signaling pathway ( 178 ). Prostaglandins have contrasting roles in the immune response.…”