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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 26, 2008; DOI: 10.1124/jpet.108.141275

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Received for publication May 20, 2008.
Revised June 21, 2008.
Accepted for publication June 25, 2008.

EP2 receptor-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

Le Yu 1, William KK Wu 1, Zhi Jie Li 1, Helen PS Wong 1, Emily KK Tai 1, Ya Chun Wu 1, Hai Tao Li 1, Chi Hin Cho 2*

1 The Chinese University of Hong Kong 2 The chinese University of Hong Kong

* Address correspondence to: E-mail: chcho{at}cuhk.edu.hk

Abstract

The use of non-steroidal 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. The precise role of PGE2 in the disease development of esophageal squamous-cell carcinoma, however, 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 PGE2 receptors, namely, EP1 to EP4 receptors. In this regard, PGE2 and the EP2 receptor agonist butaprost markedly increased HKESC-1 cell proliferation. Moreover, the mitogenic effect of PGE2 was significantly attenuated by RNA interference-mediated knockdown of 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 (MEK) inhibitor U0126. AP-1 binding inhibitor curcumin also partially reversed the mitogenic effect of PGE2. Taken together, these data demonstrate for the first time that EP2 receptor mediates the mitogenic effect of PGE2 in esophageal squamous-cell carcinoma via activation 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.


Key words: EP receptor, PGE2, activator protein-1, esophageal squamouse-cell carcinoma, extracellular signal-regulated kinase, proliferation




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