Carcinogenesis Advance Access originally published online on February 2, 2007
Carcinogenesis 2007 28(10):2063-2068; doi:10.1093/carcin/bgm011
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Prostaglandin receptor EP2 is responsible for cyclooxygenase-2 induction by prostaglandin E2 in mouse skin
The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, PO Box 389, Smithville, TX 78957, USA
* To whom correspondence should be addressed. Tel: +1 512 237 9482; Fax: +1 512 237 9566; Email: smfischer{at}mdanderson.org
The EP2 prostanoid receptor is 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 with 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 with 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.
Abbreviations: AC, adenylate cyclase; COX-2, cyclooxygenase-2; CREB, cyclic AMP response element-binding protein; EGFR, epidermal growth factor receptor; PGE2, prostaglandin E2; PKA, protein kinase A; SDS, sodium dodecyl sulphate; TPA, 12-O-tetradecanoylphorbol-13-acetate; WT, wild-type
These authors contributed equally to this work. Received August 25, 2006; revised January 9, 2007; accepted January 10, 2007.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D.-H. Kim, J.-H. Kim, E.-H. Kim, H.-K. Na, Y.-N. Cha, J. H. Chung, and Y.-J. Surh 15-Deoxy-{Delta}12,14-prostaglandin J2 upregulates the expression of heme oxygenase-1 and subsequently matrix metalloproteinase-1 in human breast cancer cells: possible roles of iron and ROS Carcinogenesis, April 1, 2009; 30(4): 645 - 654. [Abstract] [Full Text] [PDF]
|
|