Department of Medicine, Medical University of South Carolina, Charleston, 29425, USA.
Anticancer Agents Med Chem. 2011 Nov;11(9):882-90. doi: 10.2174/187152011797655168.
Almost all classes of bioactive lipids such as cholesterol and cholesterol derivatives, phospholipids and lysophospholipids, eicosanoids, and sphingolipids are critically involved in tumorigenesis. However, a systematic analysis of the distinct tumorigenic functions of lipids is rare. As a general principle, lipids either act directly by binding to receptors and other cell signaling proteins in growth control, or indirectly by regulating membrane organization such as the formation of membrane microdomains (lipid rafts) that modulate receptor or other membrane protein function. Lipid rafts are known to be formed by cholesterol and the sphingolipids or ceramide derivatives sphingomyelin and glucosylceramide (cholesterol-sphingomyelin-glucosylceramide or CSG rafts). In this review, we discuss the interconnection of sphingolipids with cholesterol and its derivatives in breast cancer drug resistance. Bile acids are cholesterol derivatives that are first synthesized in the liver (primary bile acids) and then metabolized by intestinal bacteria giving rise to secondary bile acids. They activate farnesoid X receptor (FXR), which inhibits cholesterol conversion to primary bile acids and induces the expression of drug resistance proteins. We introduce a novel model by which bile acid-mediated activation of FXR may promote the formation of CSG lipid rafts that trans-activate drug resistance proteins in breast cancer. Since breast cancer stem cells express high levels of drug resistance proteins, our model predicts that serum bile acids promote breast cancer stem cell survival and metastasis. Our model also predicts that FXR antagonists in combination with sphingolipid biosynthesis inhibitors may be promising candidates for novel drugs in lipid therapy of breast cancer.
几乎所有生物活性脂质的类别，如胆固醇和胆固醇衍生物、磷脂和溶血磷脂、类二十烷酸和鞘脂，都在肿瘤发生中起着至关重要的作用。然而，对脂质独特的致癌功能进行系统分析的情况很少见。一般来说，脂质可以通过与生长控制中的受体和其他细胞信号蛋白直接结合来发挥作用，或者通过调节膜组织，如形成调节受体或其他膜蛋白功能的膜微区（脂质筏）来间接发挥作用。已知脂质筏是由胆固醇和鞘脂或神经酰胺衍生物神经鞘磷脂和葡萄糖神经酰胺（胆固醇-神经鞘磷脂-葡萄糖神经酰胺或 CSG 筏）形成的。在这篇综述中，我们讨论了鞘脂与胆固醇及其衍生物在乳腺癌耐药性中的相互关系。胆汁酸是胆固醇的衍生物，首先在肝脏中合成（初级胆汁酸），然后被肠道细菌代谢生成次级胆汁酸。它们激活法尼醇 X 受体（FXR），抑制胆固醇转化为初级胆汁酸，并诱导耐药蛋白的表达。我们引入了一个新的模型，即胆汁酸介导的 FXR 激活可能促进 CSG 脂质筏的形成，从而转激活乳腺癌中的耐药蛋白。由于乳腺癌干细胞表达高水平的耐药蛋白，我们的模型预测血清胆汁酸促进乳腺癌干细胞的存活和转移。我们的模型还预测，FXR 拮抗剂与鞘脂生物合成抑制剂联合使用可能是脂质治疗乳腺癌的新型药物的有前途的候选药物。
