The ω-3 epoxide of eicosapentaenoic acid inhibits endothelial cell proliferation by p38 MAP kinase activation and cyclin D1/CDK4 down-regulation
The ω-3 epoxide of eicosapentaenoic acid inhibits endothelial cell proliferation by p38 MAP kinase activation and cyclin D1/CDK4 down-regulation
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DOI：
10.1111/j.1476-5381.2010.01113.x
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发表时间：
2011-03-01
影响因子：
7.3
通讯作者：
Murray, Michael
中科院分区：
文献类型：
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作者：
Cui, Pei H.;Petrovic, Nenad;Murray, Michael
研究背景与研究背景膳食摄入omega-3多不饱和脂肪酸(omega-3 PUFAs)，如二十碳五烯酸(EPA)可降低癌症风险，而花生四烯酸等omega-6多不饱和脂肪酸(omega-6 PUFAs)增加癌症风险，但其潜在机制尚不清楚。细胞色素P450(CYP)衍生的环氧化物有助于由于摄入omega-6多不饱和脂肪酸而促进肿瘤发生。因此，omega-6花生四烯酸环氧化物(EETs)通过上调细胞周期蛋白D1的表达来抑制细胞凋亡和刺激细胞增殖。本研究评估了相应的omega-3多不饱和脂肪酸环氧化物，并评估了它们在细胞增殖调节中的作用。实验研究合成了化学稳定的EPA环氧化物(形成于8，9-，11，12-，14，15-和17，18-烯键)，并在脑微血管内皮细胞bEND.3细胞中测试了与生长相关的信号通路。流式细胞仪检测细胞周期分布，免疫印迹和实时定量聚合酶链式反应检测细胞周期蛋白基因表达。结果EPA的omega-3 17，18-环氧化合物抑制细胞增殖，使细胞周期停滞于S期，下调细胞周期蛋白D1/细胞周期蛋白依赖激酶-4复合体的表达，而8，9-环氧化合物11，12-环氧化合物和14，15-环氧化合物抑制或促进细胞增殖。17，18-环氧-EPA通过激活抑制细胞生长的p38 MAP激酶而下调细胞周期蛋白D1，但交替的EPA-环氧化物不起作用。结论和应用本研究结果表明，CYP酶在omega-3烯键上形成的环氧化物可能通过下调细胞周期蛋白D1和抑制细胞增殖而发挥其作用。
BACKGROUND AND PURPOSEDietary intake of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) like eicosapentaenoic acid (EPA) decreases cancer risk, while arachidonic acid and other omega-6 PUFAs increase risk, but the underlying mechanisms are unclear. Cytochrome P450 (CYP)-derived epoxides contribute to enhanced tumourigenesis due to omega-6 PUFA intake. Thus, omega-6 arachidonic acid epoxides (EETs) inhibit apoptosis and stimulate proliferation by up-regulating cyclin D1 expression in cells. The present study evaluated the corresponding omega-3 PUFA epoxides and assessed their role in the regulation of cell proliferation.EXPERIMENTAL APPROACHFour 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 RESULTSThe omega-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 IMPLICATIONSThe present findings suggest that the epoxide formed by CYP enzymes at the omega-3 olefinic bond may contribute to the beneficial effects of omega-3 PUFA by down-regulating cyclin D1 and suppressing cell proliferation.