title: Autocrine prostaglandin E2 signaling promotes tumor cell survival and proliferation in childhood neuroblastoma.
abstract: BACKGROUND
  Prostaglandin E(2) (PGE(2)) is an important mediator in tumor-promoting inflammation. High expression of cyclooxygenase-2 (COX-2) has been detected in the embryonic childhood tumor neuroblastoma, and treatment with COX inhibitors significantly reduces tumor growth. Here, we have investigated the significance of a high COX-2 expression in neuroblastoma by analysis of PGE(2) production, the expression pattern and localization of PGE(2) receptors and intracellular signal transduction pathways activated by PGE(2).
  
  
  RESULTS
  A high expression of the PGE(2) receptors, EP1, EP2, EP3 and EP4 in primary neuroblastomas, independent of biological and clinical characteristics, was detected using immunohistochemistry. In addition, mRNA and protein corresponding to each of the receptors were detected in neuroblastoma cell lines. Immunofluorescent staining revealed localization of the receptors to the cellular membrane, in the cytoplasm, and in the nuclear compartment. Neuroblastoma cells produced PGE(2) and stimulation of serum-starved neuroblastoma cells with PGE(2) increased the intracellular concentration of calcium and cyclic AMP with subsequent phosphorylation of Akt. Addition of 16,16-dimethyl PGE(2) (dmPGE(2)) increased cell viability in a time, dose- and cell line-dependent manner. Treatment of neuroblastoma cells with a COX-2 inhibitor resulted in a diminished cell growth and viability that was reversed by the addition of dmPGE(2). Similarly, PGE(2) receptor antagonists caused a decrease in neuroblastoma cell viability in a dose-dependent manner.
  
  
  CONCLUSIONS
  These findings demonstrate that PGE(2) acts as an autocrine and/or paracrine survival factor for neuroblastoma cells. Hence, specific targeting of PGE(2) signaling provides a novel strategy for the treatment of childhood neuroblastoma through the inhibition of important mediators of tumor-promoting inflammation.
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. Agnes.Rasmuson@ki.se
authors.forename: Agnes
authors.initials: A
authors.lastname: Rasmuson
authors.forename: Anna
authors.initials: A
authors.lastname: Kock
authors.forename: Ole Martin
authors.initials: OM
authors.lastname: Fuskevåg
authors.forename: Björn
authors.initials: B
authors.lastname: Kruspig
authors.forename: Jaione
authors.initials: J
authors.lastname: Simón-Santamaría
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gogvadze
authors.forename: John Inge
authors.initials: JI
authors.lastname: Johnsen
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.forename: Baldur
authors.initials: B
authors.lastname: Sveinbjörnsson
mesh_terms: D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology*; D019898:Autocrine Communication / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D009447:Neuroblastoma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; D052246:Cyclooxygenase 2 Inhibitors; C508711:L-161982; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013876:Thiophenes; D014230:Triazoles; C046926:AH 23848; D000242:Cyclic AMP; D015232:Dinoprostone; D015064:16,16-Dimethylprostaglandin E2; D002118:Calcium