PT  - JOURNAL ARTICLE
AU  - Le Yu
AU  - William Ka Kei Wu
AU  - Zhi Jie Li
AU  - Helen Pui Shan Wong
AU  - Emily Kin Ki Tai
AU  - Hai Tao Li
AU  - Ya Chun Wu
AU  - Chi Hin Cho
TI  - 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 E<sub>2</sub> in Esophageal Squamous-Cell Carcinoma
AID  - 10.1124/jpet.108.141275
DP  - 2008 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 258--267
VI  - 327
IP  - 1
4099  - http://jpet.aspetjournals.org/content/327/1/258.short
4100  - http://jpet.aspetjournals.org/content/327/1/258.full
SO  - J Pharmacol Exp Ther2008 Oct 01; 327
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics