RETRACTED: 15-Hydroxyprostaglandin Dehydrogenase-derived 15-Keto-prostaglandin E2 Inhibits Cholangiocarcinoma Cell Growth through Interaction with Peroxisome Proliferator-activated Receptor-γ, SMAD2/3, and TAP63 Proteins (Retracted Article)

Prostaglandin E-2 (PGE(2)) 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 PGE(2), which leads to PGE(2) biotransformation. In this study, we showed that the 15-PGDH-derived 15-keto-PGE(2) is an endogenous peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand that causes PPAR-gamma dissociation from Smad2/3, allowing Smad2/3 association with the TGF-beta 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-PGE(2)-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-PGE(2)-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-PGE(2) signaling cascade that interacts with PPAR-gamma, Smad2/3, and TAP63.