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-series (PGE₁) and the 3-series (PGE₃) are considered to act as anti-cancer prostanoids. In the present study, we provide possible reasons why PGE₁ and PGE₃, but not PGE₂, exert anti-cancer effects by focusing on each diverged E-type prostanoid (EP)4 receptor-mediated signaling pathway. PGE₁, PGE₂ and PGE₃ function as full agonists in terms of G_αs- and G_αi-protein-mediated signaling. However, PGE₁ and PGE₃ 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 PGE₁ or PGE₃ almost completely reduces PGE₂-induced TCF/β-cat activity. These results provide a plausible reason why PGE₁ and PGE₃ function as anti-cancer prostanoids as a result of novel biased activity for EP4 receptors.