Abstract
Prostaglandin E2 (PGE2) is a potent lipid mediator that plays a key role in inflammation and carcinogenesis. NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of PGE2, which leads to PGE2 biotransformation. In this study, we showed that the 15-PGDH-derived 15-keto-PGE2 is an endogenous peroxisome proliferator-activated receptor-γ (PPAR-γ) ligand that causes PPAR-γ dissociation from Smad2/3, allowing Smad2/3 association with the TGF-β receptor I and Smad anchor for receptor activation and subsequent Smad2/3 phosphorylation and transcription activation in human cholangiocarcinoma cells. The 15-PGDH/15-keto-PGE2-induced Smad2/3 phosphorylation resulted in the formation of the pSmad2/3-TAP63-p53 ternary complex and their binding to the TAP63 promoter, inducing TAP63 autotranscription. The role of TAP63 in 15-PGDH/15-keto-PGE2-induced inhibition of tumor growth was further supported by the observation that knockdown of TAP63 prevented 15-PGDH-induced inhibition of tumor cell proliferation, colony formation, and migration. These findings disclose a novel 15-PGDH-mediated 15-keto-PGE2 signaling cascade that interacts with PPAR-γ, Smad2/3, and TAP63.
Highlights
Prostaglandin E2 (PGE2)3 is a potent lipid mediator in the inflammatory milieu and tumor microenvironment that plays a
This study provides novel evidence for an active role of 15-keto-PGE2 in 15-hydroxyprostaglandin dehydrogenase (15-PGDH)-mediated anti-tumor effect
We further observed that 15-keto-PGE2 is the only PPAR-␥ agonist that increases Smad2 association with TGFBRI. These findings indicate that the 15-PGDH product 15-keto-PGE2 disrupts the peroxisome proliferator-activated receptor-␥ (PPAR-␥)Smad2/3 binding complex, leading to increased Smad2/3 association with Smad anchor for receptor activation (SARA) and TGFBRI and subsequent Smad2/3 phosphorylation and activation
Summary
15-PGDH catalyzes PGE2 oxidation to form 15-keto-PGE2. Results: 15-PGDH-derived 15-keto-PGE2 is a PPAR-␥ ligand that causes Smad2/3 association with TGFBRI/SARA and induces formation of pSmad2/3-TAP63-p53 ternary complex. The role of TAP63 in 15-PGDH/15keto-PGE2-induced inhibition of tumor growth was further supported by the observation that knockdown of TAP63 prevented 15-PGDH-induced inhibition of tumor cell proliferation, colony formation, and migration These findings disclose a novel 15-PGDH-mediated 15-keto-PGE2 signaling cascade that interacts with PPAR-␥, Smad2/3, and TAP63. Anti-cancer therapeutics, such as transforming growth factor (TGF)-1, glucocorticoids, and histone deacetylase inhibitors, have been shown to exert their anti-carcinogenic activity in part through induction of 15-PGDH expression [17, 25] All of these findings point toward an important tumor suppressive function of 15-PGDH. Our data reveal a novel 15-PGDH/15keto-PGE2-mediated signaling cascade that interacts with peroxisome proliferator-activated receptor-␥ (PPAR-␥), Smad2/3, and TAP63 in human cholangiocarcinoma cells. Given that 15-PGDH converts the pro-inflammatory and pro-tumorigenic PGE2 to the anti-inflammatory and tumor-suppressive 15-keto-PGE2, induction of endogenous 15-PGDH expression or delivery of exogenous 15-PGDH/ 15-keto-PGE2 may represent promising future therapeutic interventions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
