Martin Maria Laura, Barceló-Coblijn Gwendolyn, de Almeida Rodrigo F M, Noguera-Salvà Maria Antònia, Terés Silvia, Higuera Mónica, Liebisch Gerhard, Schmitz Gerd, Busquets Xavier, Escribá Pablo V
Department of Biology, University of the Balearic Islands, Balearic Islands, Spain.
Biochim Biophys Acta. 2013 May;1828(5):1405-13. doi: 10.1016/j.bbamem.2013.01.013. Epub 2013 Jan 27.
The synthetic fatty acid 2-hydroxyoleic acid (2OHOA) is a potent antitumor drug that we rationally designed to regulate the membrane lipid composition and structure. The lipid modifications caused by 2OHOA treatments induce important signaling changes that end up with cell death (Terés et al., 2012 [1]). One of these regulatory effects is restoration of sphingomyelin levels, which are markedly lower in cancer cells compared to normal cells (Barceló-Coblijn et al., 2011 [2]). In this study, we report another important regulatory effect of 2OHOA on cancer cell membrane composition: a large increase in 2OHOA levels, accounting for ~15% of the fatty acids present in membrane phospholipids, in human glioma (SF767 and U118) and lung cancer (A549) cells. Concomitantly, we observed marked reductions in oleic acid levels and inhibition of stearoyl-CoA desaturase. The impact of these changes on the biophysical properties of the lipid bilayer was evaluated in liposomes reconstituted from cancer cell membrane lipid extracts. Thus, 2OHOA increased the packing of ordered domains and decreased the global order of the membrane. The present results further support and extend the knowledge about the mechanism of action for 2OHOA, based on the regulation of the membrane lipid composition and structure and subsequent modulation of membrane protein-associated signaling.
合成脂肪酸2-羟基油酸（2OHOA）是一种经过合理设计以调节膜脂质组成和结构的强效抗肿瘤药物。2OHOA处理引起的脂质修饰会引发重要的信号变化，最终导致细胞死亡（特雷斯等人，2012年[1]）。这些调节作用之一是鞘磷脂水平的恢复，与正常细胞相比，癌细胞中的鞘磷脂水平明显较低（巴塞罗-科布利恩等人，2011年[2]）。在本研究中，我们报告了2OHOA对癌细胞膜组成的另一个重要调节作用：在人胶质瘤（SF767和U118）和肺癌（A549）细胞中，2OHOA水平大幅增加，占膜磷脂中脂肪酸的约15%。与此同时，我们观察到油酸水平显著降低以及硬脂酰辅酶A去饱和酶受到抑制。在从癌细胞膜脂质提取物重构的脂质体中评估了这些变化对脂质双层生物物理性质的影响。因此，2OHOA增加了有序结构域的堆积并降低了膜的整体有序性。基于对膜脂质组成和结构的调节以及随后对膜蛋白相关信号的调节，目前的结果进一步支持并扩展了关于2OHOA作用机制的认识。
