Department of Anesthesiology, Clinical Research and Development, University of Colorado-Denver, 12401 East 17th Avenue, Aurora, CO 80045, USA.
Breast Cancer Res. 2010;12(2):R16. doi: 10.1186/bcr2485. Epub 2010 Mar 5.
Statins are cholesterol-lowering drugs with pleiotropic activities including inhibition of isoprenylation and reduction of signals driving cell proliferation and survival responses.
In this study we evaluated the effects of lovastatin acid and lactone on breast cancer MDAMB231 and MDAMB468 cells using a combination of proteomic and metabonomic profiling techniques.
Lovastatin inhibited proliferation of breast cancer cell lines. MDAMB231 cells were more sensitive to its effects, and in most cases lovastatin acid showed more potency towards the manipulation of protein expression than lovastatin lactone. Increased expression of Rho inhibitor GDI-2 stabilized the non-active Ras homolog gene family member A (RhoA) leading to a decreased expression of its active, membrane-bound form. Its downstream targets cofilin, CDC42 and G3BP1 are members of the GTPase family affected by lovastatin. Our data indicated that lovastatin modulated the E2F1-pathway through the regulation of expression of prohibitin and retinoblastoma (Rb). This subsequently leads to changes of E2F-downstream targets minichromosome maintenance protein 7 (MCM7) and MutS homolog 2 (MSH2). Lovastatin also regulated the AKT-signaling pathway. Increased phosphatase and tensin homolog (PTEN) and decreased DJ-1 expression lead to a down-regulation of the active pAkt. Lovastatin's involvement in the AKT-signaling pathway was confirmed by an upregulation of its downstream target, tumor progressor NDRG1. Metabolic consequences to lovastatin exposure included suppression of glycolytic and Krebs cycle activity, and lipid biosynthesis.
The combination of proteomics and metabonomics enabled us to identify several key targets essential to the antitumor activity of lovastatin. Our results imply that lovastatin has the potential to reduce the growth of breast cancer cells.
他汀类药物是具有多种作用的降胆固醇药物，包括抑制异戊烯化和减少驱动细胞增殖和存活反应的信号。
在这项研究中，我们使用蛋白质组学和代谢组学分析技术组合评估了洛伐他汀酸和内酯对乳腺癌 MDAMB231 和 MDAMB468 细胞的影响。
洛伐他汀抑制乳腺癌细胞系的增殖。MDAMB231 细胞对其作用更敏感，在大多数情况下，洛伐他汀酸对蛋白质表达的操纵比洛伐他汀内酯更有效。Rho 抑制剂 GDI-2 的表达增加稳定了非活性 Ras 同源基因家族成员 A（RhoA），导致其活性膜结合形式的表达减少。其下游靶标丝切蛋白、CDC42 和 G3BP1 是受洛伐他汀影响的 GTPase 家族成员。我们的数据表明，洛伐他汀通过调节抑素和视网膜母细胞瘤（Rb）的表达来调节 E2F1 途径。这随后导致 E2F 下游靶标微小染色体维持蛋白 7（MCM7）和 MutS 同源物 2（MSH2）的变化。洛伐他汀还调节 AKT 信号通路。磷酸酶和张力蛋白同源物（PTEN）的增加和 DJ-1 表达的减少导致活性 pAkt 的下调。洛伐他汀对 AKT 信号通路的参与通过其下游靶标肿瘤进展物 NDRG1 的上调得到证实。洛伐他汀暴露的代谢后果包括抑制糖酵解和 Krebs 循环活性以及脂质生物合成。
蛋白质组学和代谢组学的结合使我们能够确定对洛伐他汀抗肿瘤活性至关重要的几个关键靶标。我们的结果表明，洛伐他汀有可能减少乳腺癌细胞的生长。
