Abstract
Prostaglandin reductase 2 (PTGR2) is the enzyme that catalyzes 15-keto-PGE2, an endogenous PPARγ ligand, into 13,14-dihydro-15-keto-PGE2. Previously, we have reported a novel oncogenic role of PTGR2 in gastric cancer, where PTGR2 was discovered to modulate ROS-mediated cell death and tumor transformation. In the present study, we demonstrated the oncogenic potency of PTGR2 in pancreatic cancer. First, we observed that the majority of the human pancreatic ductal adenocarcinoma tissues was stained positive for PTGR2 expression but not in the adjacent normal parts. In vitro analyses showed that silencing of PTGR2 expression enhanced ROS production, suppressed pancreatic cell proliferation, and promoted cell death through increasing 15-keto-PGE2. Mechanistically, silencing of PTGR2 or addition of 15-keto-PGE2 suppressed the expressions of solute carrier family 7 member 11 (xCT) and cystathionine gamma-lyase (CTH), two important providers of intracellular cysteine for the generation of glutathione (GSH), which is widely accepted as the first-line antioxidative defense. The oxidative stress-mediated cell death after silencing of PTGR2 or addition of 15-keto-PGE2 was further abolished after restoring intracellular GSH concentrations and cysteine supply by N-acetyl-L-cysteine and 2-Mercaptomethanol. Our data highlight the therapeutic potential of targeting PTGR2/15-keto-PGE2 for pancreatic cancer.
Highlights
Pancreatic cancer is known for its poor prognosis due to its high resistance to standard chemotherapeutic treatment
To further dissect the role of Prostaglandin reductase 2 (PTGR2) in cancer biology, we examined the expression of PTGR2 in pancreatic ductal adenocarcinoma specimens from 76 patients using immunohistochemical staining
We found that majority (85.5%) of the pancreatic ductal adenocarcinoma tissues were stained positive for PTGR2 expression but not expressed in the adjacent normal parts (Fig 1), suggesting PTGR2 may play a general oncogenic role not restricted to previously reported gastric cancer
Summary
Pancreatic cancer is known for its poor prognosis due to its high resistance to standard chemotherapeutic treatment. Because it is still an obstacle detecting pancreatic cancer in its early stage, the majority of patients are diagnosed when the tumor has reached an inoperable stage [1,2,3]. 15-ketoPGE2 is a well-established endogenous ligand of peroxisome proliferator-activated receptor γ (PPARγ), which is a master regulator of adipogenesis and lipid metabolism [4, 6]. Besides the regulation of adipogenesis and lipid metabolism, extensive research has established the role of PPARγ in tumor progression and cancer metastasis [7,8,9,10,11]. PPARγ ligands, including synthetic ligands and prostaglandin metabolites, have repeatedly demonstrated to impact on cancer progression either independently or through PPARγ activation as well [12,13,14,15,16,17]
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