TY - JOUR
T1 - 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
AU - Wu, Rong
AU - Abramson, Allan L.
AU - Shikowitz, Mark J.
AU - Dannenberg, Andrew J.
AU - Steinberg, Bettie M.
PY - 2005/9/1
Y1 - 2005/9/1
N2 - Purpose: 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. Experimental Design: Immunohistochemistry, Western blotting, and real-time PCR were used to determine levels of COX-2 in papilloma and normal laryngeal tissue. Expiant 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 E 2 (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.
AB - Purpose: 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. Experimental Design: Immunohistochemistry, Western blotting, and real-time PCR were used to determine levels of COX-2 in papilloma and normal laryngeal tissue. Expiant 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 E 2 (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.
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U2 - 10.1158/1078-0432.CCR-04-2664
DO - 10.1158/1078-0432.CCR-04-2664
M3 - Article
C2 - 16144915
AN - SCOPUS:24344477064
VL - 11
SP - 6155
EP - 6161
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 17
ER -