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.
Keywords:
Cyclooxygenase (COX) Pathway; Liver Cancer; Prostaglandins; SMAD Transcription Factor; p63.
Publication types
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Research Support, N.I.H., Extramural
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Retracted Publication
MeSH terms
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Animals
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Bile Duct Neoplasms / genetics
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Bile Duct Neoplasms / metabolism*
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Bile Duct Neoplasms / pathology
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Bile Ducts, Intrahepatic / metabolism*
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Bile Ducts, Intrahepatic / pathology
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Cell Line, Tumor
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Cell Proliferation*
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Cholangiocarcinoma / genetics
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Cholangiocarcinoma / metabolism*
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Cholangiocarcinoma / pathology
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Dinoprostone / analogs & derivatives*
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Dinoprostone / genetics
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Dinoprostone / metabolism
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Humans
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Hydroxyprostaglandin Dehydrogenases / genetics
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Hydroxyprostaglandin Dehydrogenases / metabolism*
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Male
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Mice
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Mice, Inbred NOD
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Mice, SCID
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PPAR gamma / genetics
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PPAR gamma / metabolism*
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Phosphorylation / genetics
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction / genetics
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Smad2 Protein / genetics
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Smad2 Protein / metabolism*
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Smad3 Protein / genetics
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Smad3 Protein / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic / genetics
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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PPAR gamma
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Receptors, Transforming Growth Factor beta
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SMAD2 protein, human
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SMAD3 protein, human
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Smad2 Protein
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Smad3 Protein
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TP53 protein, human
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TP63 protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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15-ketoprostaglandin E2
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Hydroxyprostaglandin Dehydrogenases
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15-hydroxyprostaglandin dehydrogenase
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Dinoprostone