Atorvastatin inhibits pancreatic carcinogenesis and increases survival in LSL-KrasG12D-LSL-Trp53R172H-Pdx1-Cre mice.
Atorvastatin inhibits pancreatic carcinogenesis and increases survival in LSL-KrasG12D-LSL-Trp53R172H-Pdx1-Cre mice.
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DOI：
10.1002/mc.21916
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发表时间：
2013-09
影响因子：
4.6
通讯作者：
Yang, Guang-Yu
中科院分区：
文献类型：
--
作者：
Liao, Jie;Chung, Yeon T.;Yang, Allison L.;Zhang, Meng;Li, Haonan;Zhang, Wanying;Yan, Liang;Yang, Guang-Yu
关键词：
有几项研究支持HMG-CoA还原酶抑制剂（如阿托伐他汀）对致癌作用的作用，其中抑制参与蛋白质异戊二烯化的异戊二烯基中间体的产生起着至关重要的作用。Kras基因突变是胰腺癌中最常见的遗传学改变，Ras蛋白需要异戊烯化才能实现膜定位和活性。在本研究中，使用LSL-KrasG 12 D-LSL-Trp 53 R172 H-Pdx 1-Cre小鼠模型（称为Pankras/p53小鼠）确定阿托伐他汀对胰腺癌发生的有效性及其对蛋白质异戊二烯化的影响。五周大的Pankras/p53小鼠喂食AIN 93 M饲料或补充100 ppm阿托伐他汀的饲料。Kaplan-Meier生存分析和Log-Rank检验显示，与对照小鼠（144.9 ± 8.4天，p<0.05）相比，喂食100 ppm阿托伐他汀的小鼠（171.9 ± 6.2天）的生存期显著增加。组织学和免疫组化分析表明，阿托伐他汀治疗导致肿瘤体积和ki-67标记的细胞增殖显着减少。对原发性胰腺肿瘤和培养的小鼠胰腺癌细胞的机制研究表明，阿托伐他汀抑制了几个关键蛋白的异戊二烯化，包括Kras蛋白及其活性，在用法尼基转移酶抑制剂R115777处理的胰腺癌细胞中观察到类似的效果。基因表达谱芯片分析显示，阿托伐他汀对132个基因表达有显著调控作用，其中Waf 1 p21、cyp 51 A1和可溶性环氧化物水解酶是阿托伐他汀作用的关键靶基因，参与炎症和肿瘤的发生。这项研究表明，阿托伐他汀有可能作为一种化学预防剂对胰腺癌的发生。
There are several studies supporting the role of HMG-CoA reductase inhibitors such as atorvastatin against carcinogenesis, in which inhibiting the generation of prenyl intermediates involved in protein prenylation plays the crucial role. Mutation of Kras gene is the most common genetic alteration in pancreatic cancer and the Ras protein requires prenylation for its membrane localization and activity. In the present study, the effectiveness of atorvastatin against pancreatic carcinogenesis and its effect on protein prenylation were determined using the LSL-KrasG12D-LSL-Trp53R172H-Pdx1-Cre mouse model (called Pankras/p53 mice). Five-week-old Pankras/p53 mice were fed either an AIN93M diet or a diet supplemented with 100 ppm atorvastatin. Kaplan-Meier survival analysis with Log-Rank test revealed a significant increase in survival in mice fed 100 ppm atorvastatin (171.9 ± 6.2 days) compared to the control mice (144.9 ± 8.4 days, p<0.05). Histologic and immunohistochemical analysis showed that atorvastatin treatment resulted in a significant reduction in tumor volume and ki-67-labeded cell proliferation. Mechanistic studies on primary pancreatic tumors and the cultured murine pancreatic carcinoma cells revealed that atorvastatin inhibited prenylation in several key proteins, including Kras protein and its activities, and similar effect was observed in pancreatic carcinoma cells treated with farnesyltransferase inhibitor R115777. Microarray assay on the global gene expression profile demonstrated that a total of 132 genes were significantly modulated by atorvastatin; and Waf1p21, cyp51A1 and soluble epoxide hydrolase were crucial atorvastatin-targeted genes which involve in inflammation and carcinogenesis. This study indicates that atorvastatin has the potential to serve as a chemopreventive agent against pancreatic carcinogenesis.
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