title: Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor.
abstract: OBJECTIVE
  Pancreatic stellate cells are source of dense fibrotic stroma, a constant pathological feature of chronic pancreatitis and pancreatic adenocarcinoma. We observed correlation between levels of cyclooxygenase 2 (COX-2) and its product prostaglandin E2 (PGE2) and the extent of pancreatic fibrosis. The aims of this study were to delineate the effects of PGE2 on immortalized human pancreatic stellate cells (HPSCs) and to identify the receptor involved.
  
  
  METHODS
  Immunohistochemistry, reverse transcription-polymerase chain reaction and quantitative reverse transcription-polymerase chain reaction were used to assess COX-2, extracellular matrix, and matrix metalloproteinase gene expression. Eicosanoid profile was determined by liquid chromatography-tandem mass spectrometry. Human pancreatic stellate cell proliferation was assessed by MTS assay, migration by Boyden chamber assay, and invasion using an invasion chamber. Transient silencing was obtained by small interfering RNA.
  
  
  RESULTS
  Human pancreatic stellate cells express COX-2 and synthesize PGE2. Prostaglandin E2 stimulated HPSC proliferation, migration, and invasion and stimulated expression of both extracellular matrix and matrix metalloproteinase genes. Human pancreatic stellate cells expressed all 4 EP receptors. Only blocking the EP4 receptor resulted in abrogation of PGE2-mediated HPSC activation. Specificity of EP4 for the effects of PGE2 on stellate cells was confirmed using specific antagonists.
  
  
  CONCLUSIONS
  Our data indicate that PGE2 regulates pancreatic stellate cell profibrotic activities via EP4 receptor, thus suggesting EP4 receptor as useful therapeutic target for pancreatic cancer to reduce desmoplasia.
authors.affiliation: Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Chantale
authors.initials: C
authors.lastname: Charo
authors.forename: Vijaykumar
authors.initials: V
authors.lastname: Holla
authors.forename: Thiruvengadam
authors.initials: T
authors.lastname: Arumugam
authors.forename: Rosa
authors.initials: R
authors.lastname: Hwang
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.forename: Raymond N
authors.initials: RN
authors.lastname: Dubois
authors.forename: David G
authors.initials: DG
authors.lastname: Menter
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
authors.forename: Vijaya
authors.initials: V
authors.lastname: Ramachandran
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D034622:RNA Interference; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D009281:Naphthalenes; D010654:Phenylbutyrates; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051546:Cyclooxygenase 2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone