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

Yumi Araki; Akiko Suganami; Suzu Endo; Yuta Masuda; Keijo Fukushima; John W. Regan; Toshihiko Murayama; Yutaka Tamura; Hiromichi Fujino

doi:10.1002/1873-3468.12878

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

Yumi Araki, Akiko Suganami, Suzu Endo, Yuta Masuda, Keijo Fukushima, John W. Regan, Toshihiko Murayama, Yutaka Tamura, Hiromichi Fujino

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	3771-3780
Number of pages	10
Journal	FEBS Letters
Volume	591
Issue number	22
DOIs	https://doi.org/10.1002/1873-3468.12878
State	Published - Nov 2017

Keywords

E-type prostanoid 4 receptors
PGE
PGE
PGE
TCF/β-catenin signaling
biased ligands

ASJC Scopus subject areas

Biophysics
Structural Biology
Biochemistry
Molecular Biology
Genetics
Cell Biology

Access to Document

10.1002/1873-3468.12878

Cite this

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

abstract = "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 Gαs- and Gαi-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.",

keywords = "E-type prostanoid 4 receptors, PGE, PGE, PGE, TCF/β-catenin signaling, biased ligands",

author = "Yumi Araki and Akiko Suganami and Suzu Endo and Yuta Masuda and Keijo Fukushima and Regan, {John W.} and Toshihiko Murayama and Yutaka Tamura and Hiromichi Fujino",

note = "Funding Information: We thank Dr. Hiroyuki Fukui (Tokushima University) and Dr. Hiroyuki Mizuguchi (Osaka Otani University) for their kind suggestions. This research was supported in part by MEXT KAKENHI Grant Number JP17K08308 (JAPAN). Publisher Copyright: {\textcopyright} 2017 Federation of European Biochemical Societies",

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T1 - PGE1 and E3 show lower efficacies than E2 to β-catenin-mediated activity as biased ligands of EP4 prostanoid receptors

AU - Araki, Yumi

AU - Suganami, Akiko

AU - Endo, Suzu

AU - Masuda, Yuta

AU - Fukushima, Keijo

AU - Regan, John W.

AU - Murayama, Toshihiko

AU - Tamura, Yutaka

AU - Fujino, Hiromichi

N1 - Funding Information: We thank Dr. Hiroyuki Fukui (Tokushima University) and Dr. Hiroyuki Mizuguchi (Osaka Otani University) for their kind suggestions. This research was supported in part by MEXT KAKENHI Grant Number JP17K08308 (JAPAN). Publisher Copyright: © 2017 Federation of European Biochemical Societies

PY - 2017/11

Y1 - 2017/11

N2 - 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 Gαs- and Gαi-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.

AB - 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 Gαs- and Gαi-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.

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