PGE 1 and E 3 show lower efficacies than E 2 to β-catenin-mediated activity as biased ligands of EP4 prostanoid receptors

The 2-series of prostaglandin E (PGE ) is regarded as a pro-cancer prostanoid, whereas the 1-series (PGE ) and the 3-series (PGE ) are considered to act as anti-cancer prostanoids. In the present study, we provide possible reasons why PGE and PGE , but not PGE , exert anti-cancer effects by focusing on each diverged E-type prostanoid (EP)4 receptor-mediated signaling pathway. PGE , PGE and PGE function as full agonists in terms of G - and G -protein-mediated signaling. However, PGE and PGE function as partial agonists of T-cell factor (TCF)/β-catenin (β-cat)-mediated activity, the well-known cancer-related signaling pathway. Furthermore, pretreatment with PGE or PGE almost completely reduces PGE -induced TCF/β-cat activity. These results provide a plausible reason why PGE and PGE function as anti-cancer prostanoids as a result of novel biased activity for EP4 receptors.