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

抄録

Increases in expressions of cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E (PGE) ₂ are well known as hallmarks of colorectal cancer. These inductions of COX-2 followed by de novo synthesis of PGE₂ are mediated via activation of EP4 prostanoid receptors. Therefore, PGE₂, 2-series of PGE, is considered as pro-cancer prostanoid. However, 1- and 3-series of PGEs, PGE₁ and PGE₃ are considered to act as anti-cancer prostanoids. Given the nature of prostanoids acting as biased ligands, herein we show possible reasons why PGE₁ and PGE₃ but not PGE₂ show anti-cancer effects by focusing on each diverged EP4 receptor-mediated signalings. Although potencies of PGEs are slightly but significantly different in some cases, PGE₁, PGE₂ and PGE₃ are plausibly acting as full agonists for EP4 receptors in terms of G_αs-protein-mediated cAMP formation as well as G_αi-protein-mediated phosphorylation of ERKs. However, interestingly, PGE₁ and PGE₃ acted like partial agonists to EP4 receptor-mediated T cell factor (TCF)/β-catenin activity, yet the binding affinities of each PGEs are identical to EP4 receptors. Furthermore, pretreatment with PGE₁ or PGE₃ almost completely reduced the PGE₂-induced TCF/β-catenin-mediated transcriptional activity to the levels of the each PGE₁ or PGE₃ treated alone. Whereas PGEs-induced cAMP formation, neither PGE₁ nor PGE₃ pretreatments did not altered the PGE₂-induced cAMP formation. Thus, PGE₁ and PGE₃ are able to attenuate specifically the PGE₂-induced pro-cancer signaling; the TCF/β-catenin-mediated transcriptional activity. These results clearly explain one plausible reason why PGE₁ and PGE₃ act as anti-cancer prostanoids; not by nutritional aspect, but by novel biased activity for EP4 receptors.