Levels of cyclooxygenase-2 are increased in the oral mucosa of smokers: Evidence for the role of epidermal growth factor receptor and its ligands

Dimitrios Moraitis, Baoheng Du, Mariana S. De Lorenzo, Jay O. Boyle, Babette B. Weksler, Erik G. Cohen, John F. Carew, Nasser K. Altorki, Levy Kopelovich, Kotha Subbaramaiah, Andrew J. Dannenberg

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

Cyclooxygenase-2 (COX-2) is a promising pharmacologic target for preventing aerodigestive malignancies. In this study, we investigated the effects of tobacco smoke on the expression of COX-2 in oral mucosa. An ∼4-fold increase in amount of COX-2 mRNA was observed in the oral mucosa of active smokers versus never smokers. Thus, a series of in vitro studies were carried ont to elucidate the mechanism by which tobacco smoke induced COX-2. Treatment of a nontumorigenic oral epithelial cell line (MSK-Leuk1) with a saline extract of tobacco smoke (TS) stimulated COX-2 transcription, resulting in increased amounts of COX-2 mRNA, COX-2 protein, and prostaglandin E2 (PGE 2) synthesis. Exposure of cells to TS also caused an increase in epidermal growth factor receptor (EGFR) tyrosine kinase activity. Both an inhibitor of EGFR tyrosine kinase activity and a neutralizing anti-EGFR antibody blocked TS-mediated induction of COX-2. To define the mechanism by which TS activated EGFR, the release of amphiregulin and transforming growth factor α, two ligands of the EGFR, was measured. Exposure to TS caused a rapid increase in the release of both ligands. TS also markedly induced the expression of mRNAs for amphiregulin and transforming growth factor α. Importantly, increased expression of both ligands was also detected in the oral mucosa of active smokers. Taken together, these results suggest that activation of EGFR signaling contributes to the elevated levels of COX-2 found in the oral mucosa of smokers. Moreover, these findings strengthen the rationale for determining whether inhibitors of COX-2 or EGFR tyrosine kinase activity can reduce the risk of tobacco smoke-related malignancies of the aerodigestive tract.

Original languageEnglish (US)
Pages (from-to)664-670
Number of pages7
JournalCancer research
Volume65
Issue number2
StatePublished - Jan 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Levels of cyclooxygenase-2 are increased in the oral mucosa of smokers: Evidence for the role of epidermal growth factor receptor and its ligands'. Together they form a unique fingerprint.

Cite this