Allie M. Lee Laboratory for Cancer Research, Department of Biochemistry and Molecular Biology, College of Agriculture, Biotechnology, and Natural Resources, University of Nevada, 1664 North Virginia Street, Reno, NV 89557, USA.
Carcinogenesis. 2010 Sep;31(9):1523-30. doi: 10.1093/carcin/bgq111. Epub 2010 Jun 4.
Docosahexaenoic acid (DHA), a 22:6 n-3 polyunsaturated fatty acid, is the longest and most highly unsaturated fatty acid found in most membranes and has been shown to inhibit cancer cell growth in part by modifying cell signaling. In the current study, alterations to epidermal growth factor receptor (EGFR) signaling upon DHA supplementation are examined in A549 lung adenocarcinoma, WiDr colon carcinoma and MDA-MB-231 breast carcinoma cell lines. Interestingly, EGFR phosphorylation, most notably at the tyrosine 1068 residue, is dramatically upregulated, and EGFR association with the Sos1 guanine nucleotide exchange factor is concomitantly increased upon DHA supplementation. However, guanosine triphosphate-bound Ras and phosphorylated extracellular signal-regulated kinase (Erk)1/2 are paradoxically downregulated in the same treatments. Previous reports have noted changes in membrane microdomains upon DHA supplementation, and our findings confirmed that EGFR, but not Ras, is excluded from caveolin-rich lipid raft fractions in DHA-treated cells, resulting in a decreased association of Ras with Sos1 and the subsequent downregulation of Erk signaling. Xenografts of the A549 cell line implanted in athymic mice fed a control high-fat diet or a diet high in DHA confirmed our in vitro data. These results demonstrate for the first time a functional consequence of decreased EGFR protein in lipid raft microdomains as a result of DHA treatment in three different cancer models. In addition, we report the ability of DHA to enhance the efficacy of EGFR inhibitors on anchorage-independent cell growth (soft agar), providing evidence for the potential development of enhanced combination therapies.
二十二碳六烯酸（DHA），一种 22:6n-3 多不饱和脂肪酸，是大多数细胞膜中发现的最长和最不饱和的脂肪酸，已被证明通过改变细胞信号抑制癌细胞生长。在目前的研究中，检查二十二碳六烯酸补充对 A549 肺腺癌、WiDr 结肠癌细胞和 MDA-MB-231 乳腺癌细胞系中表皮生长因子受体（EGFR）信号的改变。有趣的是，EGFR 磷酸化，特别是在酪氨酸 1068 残基上，显著上调，并且 EGFR 与 Sos1 鸟苷酸交换因子的关联同时增加在 DHA 补充。然而，在相同的处理中，鸟嘌呤三磷酸结合的 Ras 和磷酸化细胞外信号调节激酶（Erk）1/2 被悖论地下调。以前的报告已经注意到 DHA 补充后膜微区的变化，我们的研究结果证实，EGFR 而不是 Ras，被排除在 DHA 处理细胞的富含 caveolin 的脂筏部分之外，导致 Ras 与 Sos1 的关联减少，随后 Erk 信号下调。在给予对照高脂肪饮食或富含 DHA 的饮食的无胸腺小鼠中植入 A549 细胞系的异种移植物证实了我们的体外数据。这些结果首次证明了由于三种不同的癌症模型中 DHA 处理，EGFR 蛋白在脂筏微区中的功能降低的结果。此外，我们报告了 DHA 增强 EGFR 抑制剂对锚定非依赖性细胞生长（软琼脂）的功效的能力，为增强联合治疗的潜在发展提供了证据。
