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

描述(申请人提供)：本项目的目标是研究HMG-CoA还原酶抑制剂立普妥及其与多酚E(一种标准化的茶多酚制剂)联合应用对胰腺癌发生的机理。我们的中心假设是，立普妥抑制K-ras癌基因驱动的胰腺癌的发生是通过靶向甲戊酸代谢途径，特别是通过抑制k-ras、lamins和IGF-1R蛋白的预酯化和缩聚；立普妥和多酚E联合预防胰腺癌的协同或相加作用将通过抑制花生四烯酸代谢产物和K-ras途径的下游信号(如ERK1/2和c-jun蛋白磷酸化)而产生。我们将使用胰腺癌基因工程小鼠模型(内源性和条件性敲入小鼠模型：LSL-k-RasG12D/？Trigh剂量，以及与低剂量的组合，每种药物)来验证这一假设，以测试除了每种药物对胰腺癌发生的抑制作用外，这两种药物的组合是否产生协同或相加的作用。2.验证立普妥和多酚E联合靶向甲戊酸途径、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说。用生化和免疫化学方法进一步检测从特定目标1产生的标本中k-ras蛋白、RAS和IGF-1R蛋白膜结合的活性，以及k-ras下游信号、层粘连蛋白和花生四烯酸代谢产物的活性，以揭示相关机制。此外，还将利用所选择的永生化的人胰腺管上皮细胞系及其转化的k-ras细胞系进行深入的体外机制研究。利用基因工程小鼠的分子模拟胰腺癌模型，结合化学预防药物，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.