Antagonism of the prostaglandin E2 EP1 receptor in MDCK cells increases growth through activation of Akt and the epidermal growth factor receptor (1012.6)

Prostaglandin E2 (PGE2) plays a number of roles in the kidney that are mediated by 4 classes of E‐prostanoid (EP) receptors, including EP2 and EP4, which activate adenylate cyclase (AC), EP3 that inhibits AC, and EP1, that activates Phospholipase C. Each of these receptors contributes to a number of renal diseases. Here, the role of EP1, EP2 and EP4 in mediating the effects of PGE2 on MDCK cell growth is examined. The results indicate that EP2 and EP4 contribute to the growth stimulatory effect of PGE2, unlike EP1, which is growth inhibitory. Indeed, the EP1 antagonists ONO‐8711 and SC51089 increase, rather than inhibit MDCK cell growth. Growth stimulatory effects of ONO‐8711 and SC51089 were observed in the absence of exogenous PGE2. This latter effect was prevented by the cyclooxygenase inhibitor ibuprofen, indicating that EP1 mediated growth inhibition was dependent upon endogenous PGE2. Evidence was obtained that EP1 activation results in the inhibition of Akt signaling, including the observation that 1) ONO‐8711 and SC51089 increase Akt phosphorylation, and 2) MK2206, an Akt inhibitor, prevents the increased growth caused by EP1 antagonists. In addition, evidence was obtained for the involvement of the EGF Receptor (EGFR), including the observation that 1) SC51089 increases the phosphorylation of the EGF Receptor (EGFR), and 2) the EGFR kinase inhibitor AG1478 prevents the growth stimulatory effects of ONO‐8711 and SC51089. These latter results support the hypothesis that EP1 receptor activation also affects signaling via the EGFR. Thus, EP1 receptor pharmacology may prevent aberrant growth associated with a number of renal diseases. Grant Funding Source : NIH