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.
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.
Wu
Rong
R
Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA. rwu1@lij.edu
Abramson
Allan L
AL
Shikowitz
Mark J
MJ
Dannenberg
Andrew J
AJ
Steinberg
Bettie M
BM
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
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