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Inhibition of Pancreatic Carcinoma Growth Through Enhancing ω-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase.
Anticancer Res 2019; 39(7):3651-3660AR

Abstract

BACKGROUND/AIM

Cytochrome P450 epoxygenase is a major enzyme involved in the metabolism of ω-3 polyunsaturated fatty acids (PUFAs) to produce biologically active ω-3 epoxy fatty acids (ω-3 epoxides). In general, all epoxy PUFAs including ω-3 epoxides are quickly metabolized/inactivated by soluble epoxide hydrolase (sEH) to form diol products. The aims of this study were to determine the effect and mechanism of fat-1 transgene, and ω-3 PUFA combined with sEH gene knockout or inhibitor on inhibiting pancreatic cancer and the related mechanisms involved.

MATERIALS AND METHODS

PK03-mutant KrasG12D murine pancreatic carcinoma cells were inoculated into mouse models including fat-1, sEH-/- and C57BL/6J mice. The mice were fed with AIN-76A diet with or without ω-3 PUFA supplementation or treated with sEH inhibitor. In addition to tumor growth (tumor size and weight), cell proliferation, mutant Kras-mediated signaling, inflammatory reaction and angiogenesis were analyzed immunohisto-chemically and by western blot assay. ω-3 PUFA metabolism, particularly focusing on ω-3 epoxy fatty acids (ω-3 epoxides), was measured using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach.

RESULTS

Significant decreases of weight and size of the PK03 pancreatic carcinoma were observed in the fat-1 transgenic mice treated with sEH inhibitor compared to those of C57BL/6J control mice fed with AIN-76A diet (weight: 0.28±0.04 g vs. 0.58±0.06 g; size: 187.0±17.5 mm3 vs. 519.3±60.6 mm3). In a separate experiment, sEH-/- mice fed ω-3 PUFA supplement and C57BL/6J mice treated with sEH inhibitor and fed ω-3 PUFA supplement exhibited a significant reduction in the weight and size of the pancreatic carcinoma compared to C57BL/6J control mice (weight: 0.26±.26 g and 0.39±.39 g vs. 0.69±0.11 g, respectively; size: 274.2±36.2 mm3 and 296.4±99.8 mm3 vs. 612.6±117.8 mm3, respectively). Moreover, compared to the pancreatic tumors in C57BL/6J control mice, the tumors in fat-1 transgenic mice treated with sEH inhibitor showed a significant less inflammatory cell infiltrate (62.6±9.2/HPF (high power field) vs. 8.0±1.2/HPF), tumor cell proliferation (48.5±1.7% vs. 16.5±1.6%), and angiogenesis (micro-vessel density (MVD): 35.0±1.0 vs. 11.1±0.5) immunohistochemically, as well as significantly increased caspase-3 labeled apoptosis (0.44±0.06% vs. 0.69±0.06%, respectively). Using western blot approach, significant inhibition of mutant Kras-activated signals including phosphorylated Serine/threonine kinases (cRAF), Mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK) were identified in pancreatic carcinoma of fat-1 transgenic mice treated with sEH inhibitor. Eicosanoic acid metabolic profiling of the serum specimens detected a significant increase of the ratios of epoxides to dihydroxy fatty acid (DiHDPE) for docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and epoxides/dihydroxy octadecenoic acid (DiHOME) for arachidonic acid (ARA) and linoleic acid (LA), as well as a significant increase of epoxy metabolites of DHA, EPA, ARA and LA in fat-1 transgenic mice treated with a sEH inhibitor.

CONCLUSION

ω-3 epoxy products from ω-3 PUFA metabolism play a crucial role in inhibiting pancreatic cancer growth, and use of ω-3 PUFAs combined with sEH inhibition is a strategy with high potential for pancreatic cancer treatment and prevention.

Authors+Show Affiliations

Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.Department of Entomology, University of California, Davis, CA, U.S.A.Department of Entomology, University of California, Davis, CA, U.S.A.Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A.Department of Entomology, University of California, Davis, CA, U.S.A.Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, U.S.A. g-yang@northwestern.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31262891

Citation

Xia, Rong, et al. "Inhibition of Pancreatic Carcinoma Growth Through Enhancing Ω-3 Epoxy Polyunsaturated Fatty Acid Profile By Inhibition of Soluble Epoxide Hydrolase." Anticancer Research, vol. 39, no. 7, 2019, pp. 3651-3660.
Xia R, Sun L, Liao J, et al. Inhibition of Pancreatic Carcinoma Growth Through Enhancing ω-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase. Anticancer Res. 2019;39(7):3651-3660.
Xia, R., Sun, L., Liao, J., Li, H., You, X., Xu, D., ... Yang, G. Y. (2019). Inhibition of Pancreatic Carcinoma Growth Through Enhancing ω-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase. Anticancer Research, 39(7), pp. 3651-3660. doi:10.21873/anticanres.13513.
Xia R, et al. Inhibition of Pancreatic Carcinoma Growth Through Enhancing Ω-3 Epoxy Polyunsaturated Fatty Acid Profile By Inhibition of Soluble Epoxide Hydrolase. Anticancer Res. 2019;39(7):3651-3660. PubMed PMID: 31262891.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of Pancreatic Carcinoma Growth Through Enhancing ω-3 Epoxy Polyunsaturated Fatty Acid Profile by Inhibition of Soluble Epoxide Hydrolase. AU - Xia,Rong, AU - Sun,Leyu, AU - Liao,Jie, AU - Li,Haonan, AU - You,Xiaoming, AU - Xu,Dandan, AU - Yang,Jun, AU - Hwang,Sung Hee, AU - Jones,Ryan D, AU - Hammock,Bruce, AU - Yang,Guang-Yu, PY - 2019/03/15/received PY - 2019/05/30/revised PY - 2019/06/10/accepted PY - 2019/7/3/entrez PY - 2019/7/3/pubmed PY - 2019/7/3/medline KW - Polyunsaturated fatty acid KW - epoxy fatty acid KW - fat-1 KW - pancreatic cancer KW - soluble epoxide hydrolase SP - 3651 EP - 3660 JF - Anticancer research JO - Anticancer Res. VL - 39 IS - 7 N2 - BACKGROUND/AIM: Cytochrome P450 epoxygenase is a major enzyme involved in the metabolism of ω-3 polyunsaturated fatty acids (PUFAs) to produce biologically active ω-3 epoxy fatty acids (ω-3 epoxides). In general, all epoxy PUFAs including ω-3 epoxides are quickly metabolized/inactivated by soluble epoxide hydrolase (sEH) to form diol products. The aims of this study were to determine the effect and mechanism of fat-1 transgene, and ω-3 PUFA combined with sEH gene knockout or inhibitor on inhibiting pancreatic cancer and the related mechanisms involved. MATERIALS AND METHODS: PK03-mutant KrasG12D murine pancreatic carcinoma cells were inoculated into mouse models including fat-1, sEH-/- and C57BL/6J mice. The mice were fed with AIN-76A diet with or without ω-3 PUFA supplementation or treated with sEH inhibitor. In addition to tumor growth (tumor size and weight), cell proliferation, mutant Kras-mediated signaling, inflammatory reaction and angiogenesis were analyzed immunohisto-chemically and by western blot assay. ω-3 PUFA metabolism, particularly focusing on ω-3 epoxy fatty acids (ω-3 epoxides), was measured using a liquid chromatography with tandem mass spectrometry (LC-MS/MS) approach. RESULTS: Significant decreases of weight and size of the PK03 pancreatic carcinoma were observed in the fat-1 transgenic mice treated with sEH inhibitor compared to those of C57BL/6J control mice fed with AIN-76A diet (weight: 0.28±0.04 g vs. 0.58±0.06 g; size: 187.0±17.5 mm3 vs. 519.3±60.6 mm3). In a separate experiment, sEH-/- mice fed ω-3 PUFA supplement and C57BL/6J mice treated with sEH inhibitor and fed ω-3 PUFA supplement exhibited a significant reduction in the weight and size of the pancreatic carcinoma compared to C57BL/6J control mice (weight: 0.26±.26 g and 0.39±.39 g vs. 0.69±0.11 g, respectively; size: 274.2±36.2 mm3 and 296.4±99.8 mm3 vs. 612.6±117.8 mm3, respectively). Moreover, compared to the pancreatic tumors in C57BL/6J control mice, the tumors in fat-1 transgenic mice treated with sEH inhibitor showed a significant less inflammatory cell infiltrate (62.6±9.2/HPF (high power field) vs. 8.0±1.2/HPF), tumor cell proliferation (48.5±1.7% vs. 16.5±1.6%), and angiogenesis (micro-vessel density (MVD): 35.0±1.0 vs. 11.1±0.5) immunohistochemically, as well as significantly increased caspase-3 labeled apoptosis (0.44±0.06% vs. 0.69±0.06%, respectively). Using western blot approach, significant inhibition of mutant Kras-activated signals including phosphorylated Serine/threonine kinases (cRAF), Mitogen-activated protein kinase kinase (MEK), and extracellular signal-regulated kinase (ERK) were identified in pancreatic carcinoma of fat-1 transgenic mice treated with sEH inhibitor. Eicosanoic acid metabolic profiling of the serum specimens detected a significant increase of the ratios of epoxides to dihydroxy fatty acid (DiHDPE) for docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and epoxides/dihydroxy octadecenoic acid (DiHOME) for arachidonic acid (ARA) and linoleic acid (LA), as well as a significant increase of epoxy metabolites of DHA, EPA, ARA and LA in fat-1 transgenic mice treated with a sEH inhibitor. CONCLUSION: ω-3 epoxy products from ω-3 PUFA metabolism play a crucial role in inhibiting pancreatic cancer growth, and use of ω-3 PUFAs combined with sEH inhibition is a strategy with high potential for pancreatic cancer treatment and prevention. SN - 1791-7530 UR - https://www.unboundmedicine.com/medline/citation/31262891/Inhibition_of_Pancreatic_Carcinoma_Growth_Through_Enhancing_ω_3_Epoxy_Polyunsaturated_Fatty_Acid_Profile_by_Inhibition_of_Soluble_Epoxide_Hydrolase_ L2 - http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=31262891 DB - PRIME DP - Unbound Medicine ER -