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The ω‐3 epoxide of eicosapentaenoic acid inhibits endothelial cell proliferation by p38 MAP kinase activation and cyclin D1/CDK4 down‐regulation
Author(s) -
Cui Pei H,
Petrovic Nenad,
Murray Michael
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01113.x
Subject(s) - cyclin d1 , eicosapentaenoic acid , cell growth , arachidonic acid , cyclin dependent kinase , cell cycle , polyunsaturated fatty acid , cyclin a , kinase , biology , cyclin dependent kinase 4 , cyclin , biochemistry , microbiology and biotechnology , protein kinase a , chemistry , apoptosis , cyclin dependent kinase 2 , fatty acid , enzyme
BACKGROUND AND PURPOSE Dietary intake of ω‐3 polyunsaturated fatty acids (ω‐3 PUFAs) like eicosapentaenoic acid (EPA) decreases cancer risk, while arachidonic acid and other ω‐6 PUFAs increase risk, but the underlying mechanisms are unclear. Cytochrome P450 (CYP)‐derived epoxides contribute to enhanced tumourigenesis due to ω‐6 PUFA intake. Thus, ω‐6 arachidonic acid epoxides (EETs) inhibit apoptosis and stimulate proliferation by up‐regulating cyclin D1 expression in cells. The present study evaluated the corresponding ω‐3 PUFA epoxides and assessed their role in the regulation of cell proliferation. EXPERIMENTAL APPROACH Four chemically stable EPA epoxides (formed at the 8,9‐, 11,12‐, 14,15‐ and 17,18‐olefinic bonds) were synthesized and tested against growth‐related signalling pathways in brain microvascular endothelial bEND.3 cells. Cell cycle distribution was determined by flow cytometry and cyclin gene expression by immunoblotting and real‐time PCR. The role of the p38 mitogen‐activated protein (MAP) kinase in cyclin D1 dysregulation was assessed using specific inhibitors and dominant‐negative expression plasmids. KEY RESULTS The ω‐3 17,18‐epoxide of EPA decreased cell proliferation, interrupted the cell cycle in S‐phase and down‐regulated the cyclin D1/cyclin‐dependent kinase (CDK)‐4 complex, whereas the 8,9‐, 11,12‐ and 14,15‐epoxides were either inactive or enhanced proliferation. Cyclin D1 down‐regulation by 17,18‐epoxy‐EPA was mediated by activation of the growth‐suppressing p38 MAP kinase, but the alternate EPA‐epoxides were inactive. CONCLUSIONS AND IMPLICATIONS The present findings suggest that the epoxide formed by CYP enzymes at the ω‐3 olefinic bond may contribute to the beneficial effects of ω‐3 PUFA by down‐regulating cyclin D1 and suppressing cell proliferation.