Activation of the Prostaglandin E₂ EP1 Receptor Antagonizes the Growth Stimulatory Effects of Prostaglandin E_2, a Component of the Cancer Microenvironment

Prostaglandin E₂ (PGE₂) is overproduced in a number of tumors, where it promotes tumor cell growth, angiogenesis and metastasis. The actions of PGE₂ are mediated by G protein-coupled E-prostanoid (EP) receptors, including EP1, coupled to Gq, EP2 and EP4, coupled to Gs, as well as EP3, coupled to Gi. This report is concerned with epithelial derived tumors, and thus, examines the role of EP receptors in mediating the effects of PGE₂ on the growth of a kidney epithelial cell line, MDCK. Our results indicate that activation of EP2 and EP4 by PGE₂ results in increased growth, unlike EP1, whose activation is growth inhibitory. Indeed, two EP1 antagonists (ONO-8711 and SC51089) stimulate, rather than inhibit, growth, an effect that is lost following an EP1 knockdown. ONO-8711 stimulates growth in the absence of exogenous PGE₂, presumably due to its ability to prevent the binding of endogenously produced PGE₂ to EP1. The involvement of Akt and the EGF Receptor (EGFR) in EP1 signaling is indicated by 1) the stimulatory effect ONO-8711 and SC51089 on the phosphorylation of Akt and the EGFR, 2) the ability of both MK2206, an Akt inhibitor, and AG1478, an EGFR kinase inhibitor, to prevent the increased growth caused by ONO-8711 and SC51089. Similarly, an EGFR knockdown, and a dominant negative EGFR both prevent the increased growth caused by EP1 antagonists. Of particular interest in these regards, our co-immunoprecipitation studies indicate a direct interaction between EP1 and the EGFR. These results support the hypothesis that 1) signaling via the EP1 receptor involves its interaction with the EGFR and 2) EP1 receptor pharmacology can be employed to retard the growth of carcinomas.