Abstract
Anti‐inflammatory and anti‐carcinogenic effects of ω‐3 polyunsaturated fatty acid (PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), etc., are well known; but the mechanism/s remains unclear. Of the three metabolic pathways {Cyclooxygenase (COX), Lipooxygenase (LOX) and Cyto‐p450 (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. However, under physiologic conditions, these ω‐3 epoxides are quickly inactivated by soluble epoxide hydrolase (sEH) to the diol products, and a sEH inhibitor appears crucial to stabilizing/enhancing these ω‐3 epoxides actions. In this study, using a transplantable murine PK03 pancreatic carcinoma model which carried mutant Kras gene, we have performed three animal experiments using Fat‐1 transgenic, sEH (−/−), and C57BL/6J mice subcutaneously implanted with a murine PK03 pancreatic carcinoma cells treated with or without sEH inhibitor and fed with either AIN‐76A or AIN‐76A diet supplemented with ω‐3 PUFAs. Aims of this study are to determine 1) if sEH gene knockout or inhibition stabilize the epoxide metabolites of ω‐3/ω‐6 PUFAs, 2) if sEH gene knockout or inhibition has more potent effects on inhibiting pancreatic cancer growth via enhancing the ω‐3 epoxide metabolites, and 3) potential molecular targets on mutant Kras mediated signaling, angiogenesis and inflammation. The significant findings were summarized as follows: in Fat‐1 mice treated with sEH inhibitor t‐AUCB or sEH (−/−) mice fed with AIN‐76A diet supplemented with ω‐3 PUFAs or C57BL/6J mice treated with sEH inhibitor and AIN‐76A diet supplemented with ω‐3 PUFAs, compared to fat‐1 mice without t‐AUCB treatment or sEH(−/−) mice fed with AIN‐76A diet, or C57BL/6J mice fed AIN‐76A diet, i) the size and tumor volume of xenograft PK03 pancreatic carcinoma was significantly inhibited ii) more glandular formation/well differentiation in the treated PK03 pancreatic carcinoma was observed by histopathologic analysis, iii) significant less inflammatory cell infiltrates and cell proliferation labeled immunohistochemically by anti‐myeloperoxidase and ki‐67 antibodies, as well as significant increased caspase‐3 labeled apoptosis and significant reduced intratumoral angiogenesis labeled by CD34 antibody were observed in the treated PK03 pancreatic carcinoma; iv) Western blot analysis showed a significant inhibition of mutant Kras‐activated signals including phosphorylated cRaf, MEK and ERK. Eicosanoic acid metabolic profiling analyzed by LC/MSMS method revealed a significant increase of the ratios of Epoxy to DiHDPE for DHA and EPA, and Epoxy/DiHOME for ARA and LA, as well as a significant increase of epoxy metabolites of DHA, EPA, ARA and LA. These results indicate that ω‐3 PUFAs supplementation together with sEH inhibition plays an important role in inhibiting pancreatic carcinogenesis mainly via enhancing the epoxy metabolites, and are highly potential approach for preventing pancreatic cancer.Support or Funding InformationSupported by NIH R01 DK107767 to Dr. Guang‐Yu Yang.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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