PGE 1 and E 3 show lower efficacies than E 2 to β‐catenin‐mediated activity as biased ligands of EP 4 prostanoid receptors

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