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Signaling and Regulation

Multiple Signaling Pathways Are Responsible for Prostaglandin E₂–Induced Murine Keratinocyte Proliferation

Science Park-Research Division, The University of Texas M. D. Anderson Cancer Center, Smithville, Texas

Requests for reprints: Susan M. Fischer, Science Park-Research Division, The University of Texas M. D. Anderson Cancer Center, P.O. Box 389, Smithville, TX 78957. Phone: 512-237-9482; Fax: 512-237-9566. E-mail: smfischer{at}mdanderson.org

Although prostaglandin E₂ (PGE₂) has been shown by pharmacologic and genetic studies to be important in skin cancer, the molecular mechanism(s) by which it contributes to tumor growth is not well understood. In this study, we investigated the mechanisms by which PGE₂ stimulates murine keratinocyte proliferation using in vitro and in vivo models. In primary mouse keratinocyte cultures, PGE₂ activated the epidermal growth factor receptor (EGFR) and its downstream signaling pathways as well as increased cyclic AMP (cAMP) production and activated the cAMP response element binding protein (CREB). EGFR activation was not significantly inhibited by pretreatment with a c-src inhibitor (PP2), nor by a protein kinase A inhibitor (H-89). However, PGE₂-stimulated extracellularly regulated kinase 1/2 (ERK1/2) activation was completely blocked by EGFR, ERK1/2, and phosphatidylinositol 3-kinase (PI3K) pathway inhibitors. In addition, these inhibitors attenuated the PGE₂-induced proliferation, nuclear factor-B, activator protein-1 (AP-1), and CREB binding to the promoter regions of the cyclin D1 and vascular endothelial growth factor (VEGF) genes and expression of cyclin D1 and VEGF in primary mouse keratinocytes. Similarly, in vivo, we found that WT mice treated with PGE₂ and untreated cyclooxygenase-2–overexpressing transgenic mice had higher levels of cell proliferation and expression of cyclin D1 and VEGF, as well as higher levels of activated EGFR, nuclear factor-B, AP-1, and CREB, than vehicle-treated WT mice. Our findings provide evidence for a link between cyclooxygenase-2 overexpression and EGFR-, ERK-, PI3K-, cAMP-mediated cell proliferation, and the tumor-promoting activity of PGE₂ in mouse skin. (Mol Cancer Res 2008;6(6):1003–16)