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

[Speaker] Hiromichi Fujino:1
[Co-author] Yumi Araki:1,2, Akiko Suganami:3, Suzu Endo:1, Harumi Takano:1, Yuta Masuda:1, Keijo Fukushima:1, John W Regan:4, Toshihiko Murayama:2, Yutaka Tamura:3
1:Department of Molecular Pharmacology, Tokushima University, Graduate School of Pharmaceutical Sciences, Japan, 2:Laboratory of Chemical Pharmacology, Chiba University, Graduate School of Pharmaceutical Sciences, Japan, 3:Department of Bioinformatics, Chiba University, Graduate School of Medicine, Japan, 4:Department of Pharmacology & Toxicology, The University of Arizona, College of Pharmacy, USA

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 Gαs-protein-mediated cAMP formation as well as Gαi-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.
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