PGE1 and E3 show lower efficacies than E2 to β‐catenin‐mediated activity as biased ligands of EP4 prostanoid receptors

The 2-series of prostaglandin E (PGE2) is regarded as a pro-cancer prostanoid, whereas the 1- and 3-series (PGE1 and PGE3) are considered to act as anti-cancer prostanoids. We herein provide possible reasons why PGE1 and PGE3, but not PGE2, exert anti-cancer effects by focusing on each diverged E-type prostanoid 4 (EP4) receptor-mediated signaling pathway. PGE1, PGE2, and PGE3 function as full agonists in terms of Gαs- and Gαi-protein-mediated signaling. However, PGE1 and PGE3 function as partial agonists of T-cell factor (TCF)/β-catenin-mediated activity, the well-known cancer-related signaling pathway. Furthermore, pretreatment with PGE1 or PGE3 almost completely reduces PGE2-induced TCF/β-catenin activity. These results clearly provide a plausible reason why PGE1 and PGE3 function as anti-cancer prostanoids by novel biased activity for EP4 receptors. This article is protected by copyright. All rights reserved.