HMG-CoA reductase inhibitor, tea polyphenols and pancreatic cancer prevention

描述（由申请人提供）：本项目的目的是研究HMG-CoA还原酶抑制剂立普妥及其与多酚E（一种标准化茶多酚制剂）联合应用对胰腺癌发生的基于机制的化学预防作用。我们的中心假设是立普妥抑制K-ras癌基因驱动的胰腺癌发生是通过靶向甲羟戊酸代谢途径，特别是通过抑制k-ras、核纤层蛋白和IGF-1 R蛋白的异戊烯化和长链化;立普妥和多酚E的组合对预防胰腺癌发生的协同或相加作用将通过抑制花生四烯酸代谢和降低K-ras通路的信号流（如ErK 1/2和c-Jun蛋白磷酸化）。我们将使用胰腺癌的基因工程小鼠模型（化合物内源性和条件性敲入小鼠模型：LSL-k-rasG 12 D/？每种药剂的高剂量和与低剂量的组合），以测试除了每种药剂对胰腺癌发生的抑制作用之外，药剂的组合是否产生协同或累加作用。2.验证立普妥和多酚E联合作用靶向甲羟戊酸途径、花生四烯酸代谢产物和K-ras下游信号是预防胰腺癌发生的关键分子机制的假设。将用生化和免疫化学方法进一步检查特异性Aim 1产生的标本的k-ras蛋白、Ras和IGF-1 R蛋白膜结合活性，以及k-ras下游信号、核纤层蛋白和花生四烯酸代谢产物，以揭示相关机制。此外，将在体外使用所选择的永生化人胰腺导管上皮细胞系及其k-ras转化细胞系进行深入的机制研究。本研究通过建立分子模拟胰腺癌的基因工程小鼠模型，并结合化学预防药物，为胰腺癌的预防提供了有效的策略。

DESCRIPTION (provided by applicant): The objective of this project is to study the mechanism-based chemoprevention of pancreatic carcinogenesis by HMG-CoA reductase inhibitor Lipitor and its combination with polyphenol E (a standardized tea polyphenol preparation). Our central hypothesis is that the inhibition of K-ras oncogene-driven pancreatic carcinogenesis by Lipitor is through targeting the mevalonate metabolic pathway, in particular via inhibiting prenylation and dolichylation on k-ras, lamins and IGF-1R proteins; the synergistic or additive effects on prevention of pancreatic carcinogenesis by the combination of Lipitor and polyphenol E will be produced through inhibition of arachidonic acid metabolits and down-stream signals of the K-ras pathway (such as ErK1/2 and c-Jun protein phosphorylation). We will test this hypothesis using a genetically engineered mouse model of pancreatic cancer (compound endogenously and conditionally knocked-in mouse model: LSL-k- rasG12D/?Trigh doses, and combination with low dose, of each agent) to test whether the combination of agents produces synergistic or additive effects, in addition to the inhibitory effect of each agent on pancreatic carcinogenesis. 2. Test the hypothesis that targeting the mevalonate pathway, arachidonic acid metabolits, and K-ras downstream signals by the combination of Lipitor and polyphenol E are the key molecular mechanisms in the prevention of pancreatic carcinogenesis. The specimens generated from Specific Aim 1 will be further examined for activity of k-ras protein, Ras, and IGF-1R protein membranous bound, and k-ras downstream signals, lamin and arachidonic acid metabolites with the biochemical and immunochemical approaches to reveal the mechanism involved. Furthermore, in-depth mechanistic studies will be performed using the selected immortalized human pancreatic ductal epithelial cell line and its k-ras transformed cell line in vitro. Using a genetically engineered mouse model of molecular-mimic pancreas cancer combined with chemopreventive agents, this project will be significant in the development of efficient strategy for the prevention of pancreas cancer in human.