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

15-Hydroxyprostaglandin Dehydrogenase Generation of Electrophilic Lipid Signaling Mediators from Hydroxy Ω-3 Fatty Acids

“…9) reinforces the concept that electrophilic 15PGDH metabolites can acquire additional and unique biological activities (5,6,13,19). Herein and in other 15-oxoETE, 17-oxoDHA, and 15d-PGJ 2 signaling studies, higher than physiological concentrations of the electrophile have been added to culture systems.…”

“…3D and 4D). 11,13,16,17, and 20-oxoDHA formation was also significantly inhibited in A549 cells, but not in primary AEC. This could be a result of differences in the expression of cell-specific dehydrogenase activities or the specificity of the CAY inhibitor for 15PGDH.…”

“…The hepatocellular carcinoma model determined that cell proliferation was inhibited by an increase in p21 WAF1/Cip1 (cyclin-dependent kinase inhibitor 1) expression, leading to downstream association with cyclin-dependent kinase (CDK2), CDK4, and proliferating cell nuclear antigen (12). In the cholangiocarcinoma model, inhibition of proliferation is acquired through PPAR␥-, (SMAD2/3)-, and Tap63 (tumor protein)-mediated signaling actions (13). This study also linked 15-ketoPGE 2 generation with the induction of SMAD 2/3 dissociation from PPAR␥, thus promoting SMAD 2/3 complex formation with transforming growth factor B receptor 1 and SMAD anchor receptor for acti- vation.…”

“…However, these studies only demonstrated that 15PGDH metabolites were products of the metabolism of pro-proliferative signaling molecules and not potentially conferred with alternative signaling potential. More recent studies of hepatocellular carcinoma and cholangiocarcinoma show that 15-ketoPGE 2 formation not only decreases the levels of the pro-proliferative PGE 2 but also inhibits cell growth via activation of PPAR␥ (12,13). The hepatocellular carcinoma model determined that cell proliferation was inhibited by an increase in p21 WAF1/Cip1 (cyclin-dependent kinase inhibitor 1) expression, leading to downstream association with cyclin-dependent kinase (CDK2), CDK4, and proliferating cell nuclear antigen (12).…”

“…For example, 15-ketoPGE 2 formation not only decreases the levels of the proproliferative PGE 2 but also inhibits growth of hepatocellular carcinoma and cholangiocarcinoma by peroxisome proliferator activator receptor ␥ (PPAR␥) activation (12,13). Studies in human umbilical vein endothelial cells affirm that 11-oxoETE and 15-oxoETE mediate anti-proliferative properties (5,6).…”