State Key Laboratory of Pharmaceutical Biotechnology and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
Department of Obstetrics and Gynecology, Xiamen Chang Gung Hospital, Xiamen, China.
Cancer Res Treat. 2020 Jul;52(3):815-829. doi: 10.4143/crt.2019.380. Epub 2020 Mar 5.
While numerous epidemiological studies have indicated that omega-3 polyunsaturated fatty acids have anticancer properties in various cancers, the effects and mechanisms of eicosapentaenoic acid (EPA) in ovarian cancer cell growth are poorly understood.
ES2 ovarian clear cell carcinoma cells and SKOV3 adenocarcinoma cells were treated with palmitic acid or EPA, followed by flow cytometry and cell counting to measure apoptosis and proliferation, respectively. A modified protein lipid overlay assay was used to further verify whether EPA was a ligand of G protein-coupled receptor 30 (GPR30) in ES2 cells. The levels of apoptosis-related genes, phosphorylated AKT, and phosphorylated ERK1/2 were detected to explore the underlying mechanism. Finally, inhibitory effect of EPA on tumor growth via GPR30 was determined in vitro and in vivo.
EPA suppressed ES2 ovarian clear cell carcinoma cells growth via GPR30, a novel EPA receptor, by inducing apoptosis. As a ligand of GPR30, EPA activated the GPR30-cAMP- protein kinase A signaling pathway. When GPR30 was suppressed by siRNA or its inhibitor G15, the antiproliferative action of EPA was impaired. Furthermore, EPA inhibited tumor growth by blocking the activation of AKT and ERK. In the mouse xenograft model, EPA decreased tumor volume and weight through GPR30 by blocking tumor cell proliferation.
These results confirm that EPA is a tumor suppressor in human ovarian clear cell carcinoma cells and functions through a novel fatty acid receptor, GPR30, indicating a mechanistic linkage between omega-3 fatty acids and cancers.
虽然许多流行病学研究表明ω-3 多不饱和脂肪酸在各种癌症中有抗癌特性，但人们对二十碳五烯酸（EPA）在卵巢癌细胞生长中的作用和机制知之甚少。
用棕榈酸或 EPA 处理 ES2 卵巢透明细胞癌细胞和 SKOV3 腺癌细胞，分别采用流式细胞术和细胞计数来测量细胞凋亡和增殖。采用改良的蛋白脂质覆盖测定法进一步验证 EPA 是否为 ES2 细胞中 G 蛋白偶联受体 30（GPR30）的配体。检测凋亡相关基因、磷酸化 AKT 和磷酸化 ERK1/2 的水平，以探讨其潜在机制。最后，通过体外和体内实验确定 EPA 通过 GPR30 对肿瘤生长的抑制作用。
EPA 通过诱导细胞凋亡，作为 GPR30 的配体，通过 GPR30 抑制 ES2 卵巢透明细胞癌细胞的生长。作为 GPR30 的配体，EPA 激活了 GPR30-cAMP-蛋白激酶 A 信号通路。当用 siRNA 或其抑制剂 G15 抑制 GPR30 时，EPA 的抗增殖作用受损。此外，EPA 通过阻断 AKT 和 ERK 的激活来抑制肿瘤生长。在小鼠异种移植模型中，EPA 通过阻断肿瘤细胞增殖，通过 GPR30 减少肿瘤体积和重量。
这些结果证实 EPA 是人类卵巢透明细胞癌细胞中的肿瘤抑制剂，通过一种新型的脂肪酸受体 GPR30 发挥作用，表明 ω-3 脂肪酸与癌症之间存在机制联系。
