Elevated levels of prostaglandin E(2) (PGE(2)) occur in head and neck squamous cell carcinoma (HNSCC) and have been associated with a poor prognosis. Recently, an inducible microsomal prostaglandin E synthase-1 (mPGES) was identified. This enzyme converts the cyclooxygenase product prostaglandin H(2) (PGH(2)) to PGE(2). Given the apparent significance of PGE(2) in carcinogenesis, it is important to elucidate the mechanisms that account for increased amounts of PGE(2) in HNSCC. By immunoblot analysis, mPGES was overexpressed in 11 of 14 (79%) cases of HNSCC compared with adjacent normal tissue. Immunohistochemistry localized mPGES expression to neoplastic epithelial cells. Cell culture was used to determine whether cellular transformation was associated with increased amounts of mPGES. Levels of mPGES protein and mRNA were markedly elevated in HNSCC cell lines (1483 and Ca9-22) versus a nontumorigenic oral epithelial cell line (MSK-Leuk1). Interestingly, treatment of MSK-Leuk1 cells with PGE(2) caused both dose- and time-dependent stimulation of cell growth. Each of the four known receptors for PGE(2) (E-prostanoid receptor subtypes 1-4) was detected in head and neck squamous mucosa. Taken together, these results suggest that overexpression of mPGES contributes to the increased levels of PGE(2) found in HNSCC. Additional studies will be needed to determine whether this enzyme is a bona fide target for anticancer therapy.