Carcinogenesis Advance Access published online on February 2, 2007
Carcinogenesis, doi:10.1093/carcin/bgm011
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Prostaglandin receptor EP2 is responsible for cyclooxygenase-2 induction by prostaglandin E2 in mouse skin
1 The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, U.S.A
Correspondence should be addressed to Susan M. Fischer at the University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, P.O. Box 389, Smithville, Texas 78957, U.S.A. E-mail: smfischer{at}mdanderson.org
The EP2 prostanoid receptor is a one of the four subtypes of receptors for prostaglandin E2 (PGE2). We previously reported that deletion of EP2 led to resistance to chemically-induced mouse skin carcinogenesis, whereas overexpression of EP2 resulted in enhanced tumor development. The purpose of this study was to investigate the underlying molecular mechanisms. We found that EP2 knockout mice had reduced cyclooxygenase-2 (COX-2) expression after 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment compared to wild type (WT) mice. Further, primary keratinocytes from EP2 transgenic mice had increased COX-2 expression after either TPA or PGE2 treatment and COX-2 expression was blocked by 10 µM SQ 22,536, an adenylate cyclase inhibitor. EP2 knockout mice had significantly decreased whereas EP2 transgenic mice had significantly increased PGE2 production in response to a single treatment of TPA. Cyclic AMP response element binding protein (CREB) phosphorylation was elevated to a greater extent in keratinocytes from EP2 transgenic mice compared to those of WT mice following PGE2 treatment. A protein kinase A (PKA) inhibitor reduced PGE2-mediated CREB phosphorylation in keratinocytes from EP2 transgenic mice. Furthermore, we found that there was no CREB phosphorylation in EP2 knockout mice following PGE2 treatment. PGE2-induced DNA synthesis (cell proliferation) was significantly decreased in keratinocytes from EP2 knockout mice following pretreatment with 10 µM SQ 22,536. Taken together, EP2 activation of the PKA/CREB signaling pathway is responsible for keratinocyte proliferation and our findings reveal a positive feedback loop between COX-2 and PGE2 that is mediated by the EP2 receptor.
Key Words: Prostaglandin E2 • EP2 receptor • CREB • COX-2 • skin carcinogennesis
2 Both of these authors contributed equally to this article
Received August 25, 2006; revised January 9, 2007; accepted January 10, 2007.
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