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

项目描述（申请人提供）：本项目旨在研究HMG-CoA还原酶抑制剂立普妥及其联合茶多酚E（一种标准化茶多酚制剂）对胰腺癌发生的机制化学预防作用。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、层合蛋白和IGF-1R蛋白的戊烯酰化和多酰化；通过抑制花生四烯酸代谢产物和K-ras通路下游信号（如ErK1/2和c-Jun蛋白磷酸化），立普itor与多酚E联用对预防胰腺癌的协同或叠加作用。我们将使用基因工程小鼠胰腺癌模型(复合内源性和条件敲入小鼠模型：LSL-k- rasG12D/？每种药物的三剂量和低剂量联合使用)，以测试药物联合使用除了每种药物对胰腺癌的抑制作用外，是否产生协同或加性作用。2. 验证立普妥联合多酚E靶向甲羟戊酸途径、花生四烯酸代谢物及K-ras下游信号是预防胰腺癌发生的关键分子机制。特异性Aim 1生成的标本将进一步通过生化和免疫化学方法检测k-ras蛋白、Ras和IGF-1R膜结合蛋白的活性，以及k-ras下游信号、层状蛋白和花生四烯酸代谢物的活性，以揭示其中的机制。此外，将使用所选择的永生化人胰腺导管上皮细胞系及其k-ras转化细胞系在体外进行深入的机制研究。利用分子模拟胰腺癌的基因工程小鼠模型联合化学预防药物，该项目将对开发有效的预防人类胰腺癌的策略具有重要意义。

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.