The objective of this project is to determine the role of ω-3 derived epoxy fatty acid (ω-3 epoxides) and soluble epoxide hydrolase (sEH) in mutant Kras/pancreatitis-induced carcinogenesis and to establish an efficient strategy for the prevention of pancreatic cancer using ω-3 polyunsaturated fatty acids (PUFAs) and small molecular sEH inhibitors. Anti-inflammatory/carcinogenic effects of ω-3 PUFAs are well known; but the mechanism/s remains unclear. Of the three main metabolic pathways (COX, LOX, and CYP), ω-3 PUFAs are predominantly metabolized by CYP epoxygenase/s, leading to an accumulation of ω-3 epoxy fatty acid (ω-3 epoxides); and ω-3 PUFAs are poor substrates of COX and LOX. Fat1 transgenic mouse constitutively converts ω-6 to ω-3 PUFAs in all organs. Lipid metabolomics profiling in humans with ω-3 PUFAs supplementation and in Fat1 mice further demonstrate that ω-3 epoxides are major metabolites. Functional studies indicate that ω-3 epoxides are highly potent metabolites responsible for anti-inflammatory/carcinogenic actions, possibly via targeting inflammatory signals and MAP kinase. However, under physiologic conditions, these ω-3 epoxides are quickly inactivated by sEH to the diol products, and a sEH inhibitor appears crucial to stabilizing/enhancing these ω-3 epoxides actions. Thus, we hypothesize that ω-3 epoxides are the key metabolites of ω-3 PUFAs for inhibiting inflammation and carcinogenesis via targeting Kras-activated MAP kinases and inflammation signals (NF-kB and PPARγ), and that sEH inhibition is an efficient approach to enhance these ω-3 epoxides actions against pancreatitis-induced carcinogenesis. There are three specific Aims to test our hypothesis: 1) to determine a role of Fat1 transgene, sEH gene deficiency or their combination in stabilizing and enhancing ω-3 epoxides actions against mutant Kras/pancreatitis-induced carcinogenesis in PanKras mice, 2) to determine the effectiveness of the ω-3 PUFAs combined with a highly potent sEH inhibitor as an efficient chemopreventive approach against pancreatitis-induced carcinogenesis in PanKras mice, and 3) to test our hypothesis that ω-3 epoxides are the key metabolites of ω-3 PUFAs for inhibiting pancreatic cancer via targeting mutant Kras-activated signals, inflammation signals (NF-kB and PPARγ) and angiogenesis using our unique cell models and molecular biology approaches
|Effective start/end date||4/5/16 → 3/31/21|
- National Institute of Diabetes and Digestive and Kidney Diseases (5R01DK107767-04)
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