Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48Cre/+ LSL-KrasG12D/+ mice.
Atorvastatin delays progression of pancreatic lesions to carcinoma by regulating PI3/AKT signaling in p48Cre/+ LSL-KrasG12D/+ mice.
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DOI：
10.1002/ijc.27456
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发表时间：
2012-10-15
影响因子：
6.4
通讯作者：
Rao, Chinthalapally V.
中科院分区：
文献类型：
--
作者：
Mohammed, Altaf;Qian, Li;Janakiram, Naveena B.;Lightfoot, Stan;Steele, Vernon E.;Rao, Chinthalapally V.
胰腺癌是癌症死亡的最常见原因之一，预后最差。临床观察研究表明，他汀类药物可能会降低胰腺癌的风险。在条件性p48 Cre/+-LSL-KrasG 12 D/+转基因小鼠中，评价了他汀类药物阿托伐他汀（Lipitor®）的化学预防功效和磷脂酰肌醇3-激酶（PI 3/AKT）信号传导途径对胰腺上皮内肿瘤（PanIN）向胰腺导管腺癌（PDAC）进展的作用。向六周龄雄性p48 Cre/+-LSL-KrasG 12 D/+（20只/组）小鼠饲喂含有0、200和400 ppm阿托伐他汀的AIN-76 A饮食35周。在终止时，通过免疫组织化学/荧光、ELISA、蛋白质印迹和/或逆转录-PCR方法，对胰腺的PanIN和PDAC、以及各种PI 3/AKT信号传导标志物和炎性细胞因子进行组织病理学评价。对照饮食喂养的小鼠显示85%的PDAC发生率;而阿托伐他汀喂养的小鼠显示PDAC发生率分别为65%和35%（p<0.0001）。同样，在喂食400 ppm阿托伐他汀的小鼠中观察到PanIN-3（22.6%）的显著抑制。重要的是，阿托伐他汀给药小鼠的胰腺约68%无导管病变。此外，阿托伐他汀组小鼠胰腺中PCNA、p2 X7、p-ERK、RhoA、cyclin D1、survivin、Akt、pAKT、β-catenin、cyclin E、cdK 2和caveolin-1的表达水平显著降低。此外，阿托伐他汀处理的小鼠显示出对炎性细胞因子的剂量依赖性抑制和胰腺中隧道阳性细胞、p21和PARP表达水平的显著增加。阿托伐他汀通过在临床前模型中调节PI 3/AKT信号分子，显著延迟PanIN-1和-2病变向PanIN-3和PDAC的进展，表明他汀类药物对高危胰腺癌患者的潜在临床获益。
Pancreatic cancer is the one of most common causes of cancer deaths and has the worst prognosis. Clinical observational studies suggest that statins may reduce the risk of pancreatic cancer. The chemopreventive efficacy of the statin atorvastatin (Lipitor®) and the role of the phosphatidyl-inositol 3-kinase(PI3/AKT) signaling pathway were evaluated for the progression of pancreatic intraepithelial neoplasms (PanINs) to pancreatic ductal adenocarcinoma (PDAC) in conditional p48Cre/+-LSL-KrasG12D/+ transgenic mice. Six-week old male p48Cre/+-LSL-KrasG12D/+ (20/group) mice were fed AIN-76A diets containing 0, 200, and 400 ppm atorvastatin for 35 weeks. At termination, pancreata were evaluated histopathologically for PanINs and PDAC, and for various PI3/AKT signaling markers, and inflammatory cytokines, by immunohistochemistry/immunohistoflourscence, ELISA, Western blotting and/or Reverse Transcription-PCR methods. Control diet-fed mice showed 85% incidence of PDAC; whereas, mice fed with atorvastatin showed PDAC incidence of 65 and 35% respectively (p<0.0001). Similarly, significant suppression of PanIN-3 (22.6%) was observed in mice fed 400 ppm atorvastatin. Importantly, pancreata from atorvastatin-treated mice were ~68% free from ductal lesions. Furthermore, pancreas of mice administered with atorvastatin had significantly reduced expressions levels of PCNA, p2X7, p-ERK, RhoA, cyclin D1, survivin, Akt, pAKT, β-catenin, cyclin E, cdK2, and caveolin-1. Also, atorvastatin-treated mice had shown dose-dependent suppression of inflammatory cytokines and a significant increase in tunnel-positive cells, p21 and PARP expression levels in pancreas. Atorvastatin significantly delays the progression of PanIN-1 and -2 lesions to PanIN-3 and PDAC by modulating PI3/AKT signal molecules in a preclinical model, suggesting potential clinical benefits of statins for high risk pancreatic cancer patients.
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影响因子：
5.7
作者：
Hehlgans, Stephanie;Eke, Iris;Cordes, Nils
通讯作者：
Cordes, Nils
影响因子：
8.8
作者：
Kawata, S;Yamasaki, E;Matsuzawa, Y
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Matsuzawa, Y
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作者：
Blais, L;Desgagné, A;LeLorier, J
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LeLorier, J
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29.4
作者：
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Nakamura, H
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA