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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

E Series of Prostaglandin Receptor 2-Mediated Activation of Extracellular Signal-Regulated Kinase/Activator Protein-1 Signaling Is Required for the Mitogenic Action of Prostaglandin E₂ in Esophageal Squamous-Cell Carcinoma

Departments of Pharmacology (L.Y., W.K.K.W., Z.J.L., H.P.S.W., E.K.K.T., H.T.L., Y.C.W, C.H.C.) and Medicine and Therapeutics (W.K.K.W.) and Institute of Digestive Diseases (W.K.K.W., C.H.C.), The Chinese University of Hong Kong, Hong Kong, China; and School of Basic Medical Science, Southern Medical University, Guangzhou, China (L.Y., Z.J.L.)

The use of nonsteroidal anti-inflammatory drugs is associated with a lower risk for esophageal squamous cell carcinoma, in which overexpression of cyclooxygenase-2 (COX-2) is frequently reported. Prostaglandin E₂ (PGE₂), a COX-2-derived eicosanoid, is implicated in the promotion of cancer growth. However, the precise role of PGE₂ in the disease development of esophageal squamous cell carcinoma remains elusive. In this study, we investigated the effect of PGE₂ on the proliferation of cultured esophageal squamous cell carcinoma cells (HKESC-1). Results showed that HKESC-1 cells expressed all four series of prostaglandin (EP) receptors, namely, EP1 to EP4 receptors. In this regard, PGE₂ and the EP2 receptor agonist (±)-15-deoxy-16S-hydroxy-17-cyclobutyl PGE₁ methyl ester (butaprost) markedly increased HKESC-1 cell proliferation. Moreover, the mitogenic effect of PGE₂ was significantly attenuated by RNA interference-mediated knockdown of the EP2 receptor, indicating that this receptor mediated the mitogenic effect of PGE₂. In this connection, PGE₂ and butaprost induced phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2), whose down-regulation by RNA interference significantly attenuated PGE₂-induced cell proliferation. In addition, PGE₂ and butaprost increased c-Fos expression and activator protein 1 (AP-1) transcriptional activity, which were abolished by the mitogen-activated protein kinase/Erk kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)-butadiene ethanolate (U0126). AP-1-binding inhibitor curcumin also partially reversed the mitogenic effect of PGE₂. Taken together, these data demonstrate for the first time that the EP2 receptor mediates the mitogenic effect of PGE₂ in esophageal squamous cell carcinoma via activation of the Erk/AP-1 pathway. This study supports the growth-promoting action of PGE₂ in esophageal squamous cell carcinoma and the potential application of EP2 receptor antagonists in the treatment of this disease.

Address correspondence to: Dr. Chi Hin Cho, Department of Pharmacology, 4/F Basic Medical Sciences Building, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. E-mail: chcho{at}cuhk.edu.hk