Yang Peiying, Cartwright Carrie, Chan Diana, Ding Jibin, Felix Edward, Pan Yong, Pang Jihai, Rhea Patrea, Block Keith, Fischer Susan M, Newman Robert A
Department of General Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas.
Mol Carcinog. 2014 Jul;53(7):566-77. doi: 10.1002/mc.22008. Epub 2013 Jan 31.
The beneficial effects of omega-3 fatty acids are believed to be due in part to selective alteration of arachidonate metabolism that involves cyclooxygenase (COX) enzymes. Here we investigated the effect of eicosapentaenoic acid (EPA) on the proliferation of human non-small cell lung cancer A549 (COX-2 over-expressing) and H1299 (COX-2 null) cells as well as their xenograft models. While EPA inhibited 50% of proliferation of A549 cells at 6.05 µM, almost 80 µM of EPA was needed to reach similar levels of inhibition of H1299 cells. The formation of prostaglandin (PG)E3 in A549 cells was almost threefold higher than that of H1299 cells when these cells were treated with EPA (25 µM). Intriguingly, when COX-2 expression was reduced by siRNA or shRNA in A549 cells, the antiproliferative activity of EPA was reduced substantially compared to that of control siRNA or shRNA transfected A549 cells. In line with this, dietary menhaden oil significantly inhibited the growth of A549 tumors by reducing tumor weight by 58.8 ± 7.4%. In contrast, a similar diet did not suppress the development of H1299 xenograft. Interestingly, the ratio of PGE3 to PGE2 in A549 was about 0.16 versus only 0.06 in H1299 xenograft tissues. Furthermore, PGE2 up-regulated expression of pAkt, whereas PGE3 downregulated expression of pAkt in A549 cells. Taken together, the results of our study suggest that the ability of EPA to generate PGE3 through the COX-2 enzyme might be critical for EPA-mediated tumor growth inhibition which is at least partly due to down-regulation of Akt phosphorylation by PGE3.
ω-3脂肪酸的有益作用被认为部分归因于花生四烯酸代谢的选择性改变，这涉及环氧化酶（COX）。在此，我们研究了二十碳五烯酸（EPA）对人非小细胞肺癌A549（COX-2过表达）和H1299（COX-2缺失）细胞及其异种移植模型增殖的影响。虽然EPA在6.05μM时抑制了A549细胞50%的增殖，但几乎需要80μM的EPA才能达到对H1299细胞类似的抑制水平。当用EPA（25μM）处理这些细胞时，A549细胞中前列腺素（PG）E3的形成几乎是H1299细胞的三倍。有趣的是，当通过siRNA或shRNA降低A549细胞中COX-2的表达时，与对照siRNA或shRNA转染的A549细胞相比，EPA的抗增殖活性显著降低。与此一致，饮食中的鲱鱼油通过使肿瘤重量降低58.8±7.4%，显著抑制了A549肿瘤的生长。相比之下，类似的饮食并未抑制H1299异种移植瘤的发展。有趣的是，A549中PGE3与PGE2的比率约为0.16，而在H1299异种移植组织中仅为0.06。此外，PGE2上调pAkt的表达，而PGE3下调A549细胞中pAkt的表达。综上所述，我们的研究结果表明，EPA通过COX-2酶生成PGE3的能力可能对EPA介导的肿瘤生长抑制至关重要，这至少部分归因于PGE3对Akt磷酸化的下调。
