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

Abstract

Background: T-cell lymphoma (TCL) has a very poor prognosis with limited treatment options and novel therapeutic target is urgently needed. Our previous studies have found that suppression of membrane-bound prostaglandin E2 synthase l/prostaglandin E2 (mPGES-1/PGE2) exerted anti-neoplastic effects in leukemia cells by suppressing AKT signal pathway. Here, we aim at evaluating the role and mechanism of mPGES-1/ PGE2 signaling in TCL.Methods: Expression of mPGES-1 in TCL cell line Hut78 was analyzed by Western blot and immunofluorescence. CAY10526, a selective mPGES-1 inhibitor, was used to treat Hut 78 cells. Cell viability assays was performed by using cell counting kit-8 (CCK-8). Cell apoptosis rate was examined by flow cytometer. PGE2 synthesis was detected by enzyme immunoassay (EIA). The expression of mPGES-1, cleaved caspase-3, Janus kinase/signal transduction and transcription (JAK/STAT), transforming growth factor-β (TGF-β)/Smad3 and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway of Hut 78 cells after exposed to CAY10526 was analyzed by Western blot.Results: mPGES-1 was highly expressed in Hut78 cell compared to normal peripheral blood mononuclear cells. CAY10526 inhibited cell proliferation and induced apoptosis in Hut78 cells. These effects may be partially attributed to the activation of the Caspase family and the inhibition of JAK/STAT, TGF-β/ Smad3 and PI3K/AKT signal pathways.Conclusions: Our results suggested that mPGES-1/PGE2 could be a potential therapeutic target for TCL.

Identification and partial characterization of new cell density-dependent nucleocytoplasmic shuttling proteins and open chromatin

“…PTGES3 (also known as mPGES-1), Prostaglandin E synthase 3, also plays a role in the regulation of gene expression through its ability to produce prostaglandin E2. This can activate various signaling pathways and modulate the activity of transcription factors 34 . CBFB, the core-binding factor subunit beta, forms a complex with RUNX family proteins, modulating the transcription of target genes involved in the development of various tissues 23 .…”

Cooperation between Prostaglandin E2 and Epidermal Growth Factor Receptor in Cancer Progression: A Dual Target for Cancer Therapy

“…Several molecular mechanisms have been proposed to justify the protumoral activity of PGE2. In vitro and in vivo studies demonstrate that PGE2 may induce epigenetic modifications that contribute to the growth and metastasis formation of breast and gastric cancer [ 22 , 23 ], promote miRNA modifications that contribute to modulate cancer cell growth and migration and tumor angiogenesis [ 24 , 25 , 26 , 27 ], and increases cancer cell growth, migration, and resistance to apoptosis through the modulation of several molecular pathways, such as JAK/STAT [ 28 ], PI3K/AKT [ 29 ], and RAS/Raf/MAPK signaling [ 30 ]. Moreover, PGE2 is involved in cancer immunomodulation, as previously reviewed [ 21 ].…”