title: Prostaglandin reductase 2 modulates ROS-mediated cell death and tumor transformation of gastric cancer cells and is associated with higher mortality in gastric cancer patients.
abstract: Various prostanoids and peroxisome proliferator-activated receptor γ (PPARγ) ligands play an important role in gastric cancer. Previously, we demonstrated that prostaglandin reductase 2 (PTGR2) catalyzes the reduction of the PPARγ ligand 15-keto-PGE(2) into 13,14-dihydro-15-keto-PGE(2). Here, we present functional data and clinical relevance for the role of PTGR2 in gastric cancer. Using lentiviral technology in AGS and SNU-16 gastric cancer cell lines, we either down-regulated or overexpressed PTGR2. In vitro analysis showed that PTGR2 knockdown resulted in decreased proliferation rate and colony formation, and in vivo xenograft models showed slower growth of tumors. Mechanistically, PTGR2 knockdown induced cell death, altered mitochondrial function, and increased reactive oxygen species production, which led to activation of ERK1/2 and caspase 3, with increased Bcl-2 and suppressed Bax expression. PTGR2 overexpression showed the opposite outcomes. Clinically, immunopathological staining showed strong PTGR2 expression in the gastric tumor portion, relative to nearby nontumor portions, and its expression negatively correlated with survival of patients with intestinal-type gastric cancer. Finally, in contrast to PTGR2-overexpressing cells, PTGR2-knockdown cells were more sensitive to cisplatin and 5-fluorouracil. Taken together, our findings not only provide functional and mechanistic evidence of the involvement of PTGR2 in gastric cancer, but also provide clinical observations affirming the significance of PTGR2 in gastric cancer and suggesting that PTGR2-target based therapy is worth further evaluation.
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Emily Yun-Chia
authors.initials: EY
authors.lastname: Chang
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Tsai
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.forename: Siow-Wey
authors.initials: SW
authors.lastname: Hee
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chang
authors.forename: Yun-Chih
authors.initials: YC
authors.lastname: Tsai
authors.forename: Jaw-Shiun
authors.initials: JS
authors.lastname: Tsai
authors.forename: Hsian-Ju
authors.initials: HJ
authors.lastname: Chen
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Chou
authors.forename: Shih-Yao
authors.initials: SY
authors.lastname: Lin
authors.forename: Lee-Ming
authors.initials: LM
authors.lastname: Chuang
mesh_terms: D011452:15-Oxoprostaglandin 13-Reductase; D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality* / Q000473:pathology*; D016019:Survival Analysis
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D000426:Alcohol Dehydrogenase; D011452:15-Oxoprostaglandin 13-Reductase; C485698:PTGR2 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D002945:Cisplatin; D005472:Fluorouracil