Abstract
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.
Footnotes
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This work was supported by The Hong Kong Research Grants Council (CUHK 7499/05M).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.141275.
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ABBREVIATIONS: NSAIDs, nonsteroidal anti-inflammatory drugs; COX, cyclooxygenase; PG, prostaglandin; Erk, extracellular signal-regulated kinase; Akt, protein kinase B; EP, E series of prostaglandin; butaprost, (±)-15-deoxy-16S-hydroxy-17-cyclobutyl PGE1 methyl ester; sulprostone, 16-phenoxy-ω-17,18,19,20-tetranor-prostaglandin E2-methylsulfonylamide; PGE1 alcohol, 1-hydroxy prostaglandin E1; siRNA, small interference RNA; ONO-DI-004, 17S-17,20-dimethyl-2,5,-ethano-6-oxo PGE1; ONO-AE3-208, 2-(2-(2-methyl-2-naphth-1-ylacetylamino)-phenylmethyl)-benzoic acid; RT-PCR, reverse transcription-polymerase chain reaction; PMA, phorbol 12-myristate 13-acetate; IBMX, 1-methyl-3-isobutylxanthine; JNK, c-Jun amino-terminal kinase; MAPK, mitogen-activated protein kinase; AP-1, activator protein 1; U0126, 1,4-diamino-2,3-dicyano-1,4-bis-(o-aminophenylmercapto)butadiene ethanolate; MEK, MAPK/Erk kinase; SC-236, 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-benzenesulfonamide; L-748706, 3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl-2-(5H)-furanone; forskolin, 7β-acetoxy-8,13-epoxy-1α,6β,9α-trihydroxylabd-14-en-11-one; ONO-AE3-240, 2-[2-{[4-methyl-2-(1-naphthyl)pentanoyl]amino}-4-(1H-pyrazol-1-ylmethyl)benzyl]benzoic.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received May 19, 2008.
- Accepted June 25, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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