Menendez Javier A, Vellon Luciano, Colomer Ramon, Lupu Ruth
Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA.
J Natl Cancer Inst. 2005 Nov 2;97(21):1611-5. doi: 10.1093/jnci/dji343.
The omega-6 polyunsaturated fatty acid gamma-linolenic acid (GLA; 18:3n-6), which is found in several plant oils and is used as an herbal medicine, has antitumor activity in vitro. We examined the effect of GLA on the expression of the Her-2/neu (erbB-2) oncogene, which is involved in development of numerous types of human cancer. Flow cytometric and immunoblotting analyses demonstrated that GLA treatment substantially reduced Her-2/neu protein levels in the Her-2/neu-overexpressing cell lines BT-474, SK-Br3, and MDA-MB-453 (breast cancer), SK-OV3 (ovarian cancer), and NCI-N87 (gastrointestinal tumor derived). GLA exposure led to a dramatic decrease in Her-2/neu promoter activity and a concomitant increase in the levels of polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/neu, in these cell lines. In transient transfection experiments, a Her-2/neu promoter bearing a PEA3 site-mutated sequence was not subject to negative regulation by GLA in Her-2/neu-overexpressing cell lines. Concurrent treatments of Her-2/neu-overexpressing cancer cells with GLA and the anti-Her-2/neu antibody trastuzumab led to synergistic increases in apoptosis and reduced growth and colony formation.
ω-6多不饱和脂肪酸γ-亚麻酸（GLA；18:3n-6）存在于多种植物油中，并被用作草药，它在体外具有抗肿瘤活性。我们研究了GLA对Her-2/neu（erbB-2）癌基因表达的影响，该基因与多种类型的人类癌症发展有关。流式细胞术和免疫印迹分析表明，GLA处理显著降低了Her-2/neu过表达细胞系BT-474、SK-Br3和MDA-MB-453（乳腺癌）、SK-OV3（卵巢癌）以及NCI-N87（胃肠道肿瘤来源）中的Her-2/neu蛋白水平。在这些细胞系中，GLA暴露导致Her-2/neu启动子活性显著降低，同时Her-2/neu的转录抑制因子多瘤病毒增强子激活因子3（PEA3）水平升高。在瞬时转染实验中，带有PEA3位点突变序列的Her-2/neu启动子在Her-2/neu过表达细胞系中不受GLA的负调控。用GLA和抗Her-2/neu抗体曲妥珠单抗同时处理Her-2/neu过表达的癌细胞，可协同增加细胞凋亡，并减少生长和集落形成。
