title: Prostaglandin E2 stimulates normal bronchial epithelial cell growth through induction of c-Jun and PDK1, a kinase implicated in oncogenesis.
abstract: BACKGROUND
  Cyclooxygenase-2-derived prostaglandin E2 (PGE2), a bioactive eicosanoid, has been implicated in many biological processes including reproduction, inflammation and tumor growth. We previously showed that PGE2 stimulated lung cancer cell growth and progression through PGE2 receptor EP2/EP4-mediated kinase signaling pathways. However, the role of PGE2 in controlling lung airway epithelial cell phenotype remains unknown. We evaluated the effects of c-Jun and 3-phosphoinositede dependent protein kinase-1 (PDK1) in mediating epithelial cell hyperplasia induced by PGE2.
  
  
  METHODS
  The bronchial epithelial cell lines BEAS-2B and HBEc14-KT were cultured and then treated with PGE2. PDK1 small interfering RNA (siRNA) and a PDK1 inhibitor, an antagonist of the PGE2 receptor subtype EP4 and EP4 siRNA, c-Jun siRNA, and overexpressions of c-Jun and PDK1 have been used to evaluate the effects on cell proliferation.
  
  
  RESULTS
  We demonstrated that PGE2 increased normal bronchial epithelial cell proliferation through induction of PDK1, an ankyrin repeat-containing Ser/Thr kinase implicated in the induction of apoptosis and the suppression of tumor growth. PDK1 siRNA and a PDK1 inhibitor blocked the effects of PGE2 on normal cell growth. The PGE2-induced PDK1 expression was blocked by an antagonist of the PGE2 receptor subtype EP4 and by EP4 siRNA. In addition, we showed that induction of PDK1 by PGE2 was associated with induction of the transcription factor, c-Jun protein. Silencing of c-Jun using siRNA and point mutations of c-Jun sites in the PDK1 gene promoter resulted in blockade of PDK1 expression and promoter activity induced by PGE2. In contrast, overexpression of c-Jun induced PDK1 gene promoter activity and expression followed increased cell proliferation.
  
  
  CONCLUSIONS
  PGE2 increases normal bronchial epithelial cell proliferation through increased PDK1 gene expression that is dependent on EP4 and induction of c-Jun. Therewith, our data suggest a new role of c-Jun and PDK1 in mediating epithelial cell hyperplasia induced by PGE2.
authors.affiliation: Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China. 350177646@qq.com.|Department of Radiotherapy, Sichuan Cancer Hospital, Chengdu, Sichuan Province, 610041, China. 350177646@qq.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China. doctordream@163.com.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China. wang2ke@126.com.
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: C545650:PTGER4 protein, human; D011448:Prostaglandin Antagonists; D047428:Protein Kinase Inhibitors; D058309:Receptors, Prostaglandin E, EP4 Subtype; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D015232:Dinoprostone