title: Epidermal growth factor-induced cyclooxygenase-2 expression is mediated through phosphatidylinositol-3 kinase, not mitogen-activated protein/extracellular signal-regulated kinase kinase, in recurrent respiratory papillomas.
abstract: OBJECTIVE
  Recurrent respiratory papillomas, caused by human papillomaviruses, are premalignant tumors that overexpress the epidermal growth factor receptor (EGFR). The goals of this study were as follows: (a) to evaluate the expression of cyclooxygenase-2 (COX-2) in papillomas, (b) to investigate the role of EGFR signaling in COX-2 expression, and (c) to determine whether COX-2 activity is important for the growth of papilloma cells.
  
  
  METHODS
  Immunohistochemistry, Western blotting, and real-time PCR were used to determine levels of COX-2 in papilloma and normal laryngeal tissue. Explant cultures of both normal laryngeal and papilloma cells were used to define the signaling pathways that regulate COX-2 expression and investigate the potential of targeting COX-2 as a strategy to suppress papilloma growth.
  
  
  RESULTS
  COX-2 levels were markedly increased in papillomas. In vitro studies suggested that overexpression in papillomas reflected activation of EGFR-->phosphatidylinositol 3-kinase signaling. Treatment with prostaglandin E2 (PGE2) induced COX-2, whereas celecoxib, a selective COX-2 inhibitor, suppressed levels of COX-2, suggesting a positive feedback loop. Moreover, treatment with PGE2 stimulated papilloma cell growth, whereas celecoxib suppressed proliferation and induced apoptosis.
  
  
  CONCLUSIONS
  Overexpression of COX-2 in papillomas seems to be a consequence of enhanced EGFR-->phosphatidylinositol 3-kinase signaling. We propose a positive feedback loop for COX-2 expression, with induction of COX-2 resulting in enhanced PGE2 synthesis and further expression of COX-2 that contributes to the growth of papillomas in vivo. These data strengthen the rationale for evaluating whether nonsteroidal anti-inflammatory drugs, prototypic COX inhibitors, will be useful in the management of respiratory papillomas.
authors.affiliation: Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA. rwu1@lij.edu
authors.forename: Rong
authors.initials: R
authors.lastname: Wu
authors.forename: Allan L
authors.initials: AL
authors.lastname: Abramson
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shikowitz
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
authors.forename: Bettie M
authors.initials: BM
authors.lastname: Steinberg
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D007124:Immunoenzyme Techniques; D007822:Laryngeal Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000821:virology; D007830:Larynx / Q000378:metabolism; D008565:Membrane Proteins; D009364:Neoplasm Recurrence, Local / Q000201:enzymology* / Q000821:virology; D010212:Papilloma / Q000201:enzymology* / Q000821:virology; D027383:Papillomaviridae / Q000302:isolation & purification; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D012142:Respiratory Tract Neoplasms / Q000201:enzymology* / Q000821:virology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000068579:Celecoxib; D015232:Dinoprostone