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

HMG-CoA reductase inhibitor, tea polyphenols and pancreatic cancer prevention
HMG-CoA还原酶抑制剂、茶多酚与胰腺癌预防
批准号：
7434507
负责人：
Guang-Yu Yang
金额：
$21.14万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
项目状态：
已结题
起止时间：
2007-06-01 至 2009-05-31
来源：
https://reporter.nih.gov/project-details/7434507
关键词：
AbbreviationsAddressAdenocarcinomaAnimal ModelAntibodiesApoptosisArachidonate 5-LipoxygenaseArachidonic AcidsBile fluidBindingBiochemicalBiological MarkersCancer Cell GrowthCell LineCell ProliferationCellsChemopreventionChemopreventive AgentCholesterolClinicalCoenzyme ADataDepthDevelopmentDinoprostoneDoseDuctal Epithelial CellElectrocardiogramEpidemiologic StudiesEpigallocatechin GallateEventExhibitsFutureGene MutationGenetically Engineered MouseGreen teaHumanHydroxymethylglutaryl-CoA Reductase InhibitorsHydroxymethylglutaryl-CoA reductaseImmunohistochemistryIn VitroInsulin-Like-Growth Factor I ReceptorJUN geneK-ras GeneK-ras OncogeneKnock-in MouseLaminsLectinLesionLinkMalignant neoplasm of pancreasMembraneMetabolic PathwayMetastatic Neoplasm to the LiverModelingMolecularMolecular ModelsMolecular TargetMusMutationNuclearNuclear LaminOxidoreductasePTGS2 genePancreasPancreatic Ductal AdenocarcinomaPancreatic Intraepithelial NeoplasiaPathway interactionsPhosphorylationPreparationPreventionPrevention strategyPrincipal InvestigatorProductionProtein IsoprenylationProteinsProto-Oncogene Proteins c-junSignal TransductionSpecimenStreamTP53 geneTeaTestingTobacco-Associated CarcinogenTransformed Cell LineWestern BlottingYangatorvastatinbasebreast intraductal proliferative lesioncancer preventioncarcinogenesiscyclooxygenase 2designdriving forceepicatechinepicatechin gallategallocatecholgeranylgeranyl pyrophosphateglycosylationhuman studyinterestintraepitheliallung tumorigenesismevalonatemouse modelmutantp21 K-Ras Proteinpolyphenolprelamin Aprenylationprogramsras Proteinstumor

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中文摘要
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英文摘要
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.
期刊论文(6)
专著(0)
科研奖励(0)
会议论文
Atorvastatin inhibits pancreatic carcinogenesis and increases survival in LSL-KrasG12D-LSL-Trp53R172H-Pdx1-Cre mice.
DOI： 10.1002/mc.21916
发表时间： 2013-09
期刊： MOLECULAR CARCINOGENESIS
影响因子： 4.6
作者： [Liao, Jie, Chung, Yeon T., Yang, Allison L., Zhang, Meng, Li, Haonan, Zhang, Wanying, Yan, Liang, Yang, Guang-Yu]
通讯作者： Yang, Guang-Yu
CAAX-box protein, prenylation process and carcinogenesis.
DOI： --
发表时间： 2009-05
期刊： American journal of translational research
影响因子： 2.2
作者： [Juehua Gao;J. Liao;Guang-Yu Yang]
通讯作者： Juehua Gao;J. Liao;Guang-Yu Yang
Knockdown or inhibition of aldo-keto reductase 1B10 inhibits pancreatic carcinoma growth via modulating Kras-E-cadherin pathway.
DOI： 10.1016/j.canlet.2014.09.031
发表时间： 2014-12-28
期刊： CANCER LETTERS
影响因子： 9.7
作者： [Zhang, Wanying, Li, Haonan, Yang, Yihe, Liao, Jie, Yang, Guang-Yu]
通讯作者： Yang, Guang-Yu
Omega-3 derived epoxy fatty acids and sEH in pancreatitis-induced carcinogenesis
Inhibition of pancreatic carcinogenesis via targeting c-Raf and sEH
Inhibition of pancreatic carcinogenesis via targeting c-Raf and sEH
Inhibition of pancreatic carcinogenesis via targeting c-Raf and sEH
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