Oleate promotes the proliferation of breast cancer cells via the G protein-coupled receptor GPR40
Oleate promotes the proliferation of breast cancer cells via the G protein-coupled receptor GPR40
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DOI：
10.1074/jbc.m410922200
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发表时间：
2005-04-08
影响因子：
4.8
通讯作者：
Prentki, M
中科院分区：
文献类型：
--
作者：
Hardy, S;St-Onge, GG;Prentki, M
来自流行病学研究和动物模型的证据表明，高水平的膳食脂肪摄入与乳腺癌风险之间存在联系。此外，循环脂质升高的肥胖症与各种癌症的风险增加有关。相对于这一点，我们以前表明，油酸刺激乳腺癌细胞的增殖和磷脂酰肌醇3-激酶在这一过程中发挥作用。尽管如此，关于油酸促进乳腺癌细胞生长的确切机制仍存在疑问。GTP结合蛋白G（i）/G（o）、磷脂酶C、Src和促分裂细胞外信号调节激酶1/2（MEK 1/2）的药理学抑制剂可降低乳腺癌细胞系MDA-MB-231中油酸诱导的[H-3]胸苷掺入。此外，油酸引起胞质Ca 2+的快速和短暂的上升和蛋白激酶B磷酸化的增加。在这些细胞中过表达的G蛋白偶联受体GPR 40，脂肪酸受体，放大油酸诱导的增殖，而沉默的GPR 40基因使用RNA干扰降低it. Overexpressing GPR 40在T47 D和MCF-7乳腺癌细胞是油酸反应不良允许一个强大的油酸增殖作用。这些数据表明，磷脂酶C，MEK 1/2，Src，和磷脂酰肌醇3-激酶/蛋白激酶B信号传导途径参与油酸诱导的增殖信号，这些作用至少部分通过G蛋白偶联受体GPR 40介导。结果表明，GPR 40与脂肪酸控制乳腺癌细胞生长有关，GPR 40可能提供脂肪和癌症之间的联系。
Evidence from epidemiological studies and animal models suggests a link between high levels of dietary fat intake and risk of breast cancer. In addition, obesity, in which circulating lipids are elevated, is associated with increased risk of various cancers. Relative to this point, we previously showed that oleate stimulates the proliferation of breast cancer cells and that phosphatidylinositol 3-kinase plays a role in this process. Nonetheless, questions remain regarding the precise mechanism(s) by which oleate promotes breast cancer cell growth. Pharmacological inhibitors of the GTP-binding proteins G(i)/G(o), phospholipase C, Src, and mitogenic-extracellular signal-regulated kinase 1/2 (MEK 1/2) decreased oleate-induced [H-3]thymidine incorporation in the breast cancer cell line MDA-MB-231. In addition, oleate caused a rapid and transient rise in cytosolic Ca2+ and an increase in protein kinase B phosphorylation. Overexpressing in these cells the G protein-coupled receptor GPR40, a fatty acid receptor, amplified oleate-induced proliferation, whereas silencing the GPR40 gene using RNA interference decreased it. Overexpressing GPR40 in T47D and MCF-7 breast cancer cells that are poorly responsive to oleate allowed a robust proliferative action of oleate. The data indicate that the phospholipase C, MEK 1/2, Src, and phosphatidylinositol 3-kinase/protein kinase B signaling pathways are implicated in the proliferative signal induced by oleate and that these effects are mediated at least in part via the G protein-coupled receptor GPR40. The results suggest that GPR40 is implicated in the control of breast cancer cell growth by fatty acids and that GPR40 may provide a link between fat and cancer.