Chimento Adele, Casaburi Ivan, Avena Paola, Trotta Francesca, De Luca Arianna, Rago Vittoria, Pezzi Vincenzo, Sirianni Rosa
Department of Pharmacy and Health and Nutritional Sciences, University of Calabria, Cosenza, Italy.
Front Endocrinol (Lausanne). 2019 Jan 21;9:807. doi: 10.3389/fendo.2018.00807. eCollection 2018.
Cholesterol is essential for cell function and viability. It is a component of the plasma membrane and lipid rafts and is a precursor for bile acids, steroid hormones, and Vitamin D. As a ligand for estrogen-related receptor alpha (ESRRA), cholesterol becomes a signaling molecule. Furthermore, cholesterol-derived oxysterols activate liver X receptors (LXRs) or estrogen receptors (ERs). Several studies performed in cancer cells reveal that cholesterol synthesis is enhanced compared to normal cells. Additionally, high serum cholesterol levels are associated with increased risk for many cancers, but thus far, clinical trials with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have had mixed results. Statins inhibit cholesterol synthesis within cells through the inhibition of HMG-CoA reductase, the rate-limiting enzyme in the mevalonate and cholesterol synthetic pathway. Many downstream products of mevalonate have a role in cell proliferation, since they are required for maintenance of membrane integrity; signaling, as some proteins to be active must undergo prenylation; protein synthesis, as isopentenyladenine is an essential substrate for the modification of certain tRNAs; and cell-cycle progression. In this review starting from recent acquired findings on the role that cholesterol and its metabolites fulfill in the contest of cancer cells, we discuss the results of studies focused to investigate the use of statins in order to prevent cancer growth and metastasis.
胆固醇对于细胞功能和生存能力至关重要。它是质膜和脂筏的组成部分，也是胆汁酸、类固醇激素和维生素D的前体。作为雌激素相关受体α（ESRRA）的配体，胆固醇成为一种信号分子。此外，胆固醇衍生的氧化甾醇可激活肝脏X受体（LXRs）或雌激素受体（ERs）。在癌细胞中进行的多项研究表明，与正常细胞相比，胆固醇合成增强。此外，高血清胆固醇水平与多种癌症风险增加相关，但迄今为止，使用3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）的临床试验结果不一。他汀类药物通过抑制HMG-CoA还原酶（甲羟戊酸和胆固醇合成途径中的限速酶）来抑制细胞内的胆固醇合成。甲羟戊酸的许多下游产物在细胞增殖中发挥作用，因为它们是维持膜完整性所必需的；信号传导方面，一些要发挥活性的蛋白质必须进行异戊二烯化；蛋白质合成方面，异戊烯腺嘌呤是某些tRNA修饰的必需底物；以及细胞周期进程。在这篇综述中，我们从最近获得的关于胆固醇及其代谢产物在癌细胞环境中所起作用的研究结果出发，讨论了旨在研究使用他汀类药物预防癌症生长和转移的研究结果。
