Aldo-keto reductase family 1 member B10 AKR1B10 in pancreatic carcinogenesis

醛酮还原酶家族 1 成员 B10 AKR1B10 在胰腺癌发生中的作用

• 批准号: 8682793
• 负责人: Guang-Yu Yang
• 金额: $ 31.09万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-09 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8682793
• 关键词: Affect; All-Trans-Retinol; Alleles; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Apoptosis; Biological Markers; Caerulein; Carcinoma; Chemopreventive Agent; Cholesterol; Data; Development; Diclofenac; Diet; Dose; Down-Regulation; Ensure; Exhibits; Family; Farnesol; Fat-Soluble Vitamin; Fatty Acids; Gene Mutation; Genes; Genetically Engineered Mouse; Homeostasis; Human; Induction of Apoptosis; Inflammation; Knock-out; Laboratories; Lesion; Lung; Malabsorption Syndromes; Malignant Epithelial Cell; Malignant neoplasm of pancreas; Malnutrition; Metabolism; Modeling; Mus; Mutation; NADP; Normal tissue morphology; Oncogenic; Oxidoreductase; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatic carcinoma; Pancreatitis; Patients; Pharmaceutical Preparations; Premalignant; Prevention strategy; Primary carcinoma of the liver cells; Protein Isoprenylation; Proteins; Retinal; Risk Factors; Role; Small Interfering RNA; Smoker; Smoking; Stem cells; Substrate Specificity; Sulindac; Supplementation; Testing; Tissues; Transgenic Organisms; Tretinoin; Tumor Tissue; Vitamin A; Vitamin A Deficiency; carcinogenesis; chronic pancreatitis; design; farnesyl pyrophosphate; geranylgeraniol; geranylgeranyl pyrophosphate; hydroxyl group; inhibitor/antagonist; isoprenoid; member; mouse model; mutant; neoplastic; neoplastic cell; novel; pancreatic neoplasm; prenylation; success; tandem mass spectrometry; tumor

DESCRIPTION (provided by applicant): The objective of this project is to determine the role of aldo-keto reductase family 1 member B10 (AKR1B10) in pancreatic carcinogenesis and to establish an efficient strategy for the prevention of pancreatic cancer using a potent AKR1B10 inhibitor. AKR1B10 belongs to the aldo-keto reductase (AKR) family and is a unique tumor biomarker that is over-expressed in smoking-related carcinomas including pancreas. AKR1B10 exhibits more restricted substrate specificity than that of most human AKR: only farnesal, geranylgeranial, retinal and carbonyls are its specific substrates. AKR1B10 could promote carcinogenesis in several ways, including regulating cellular fatty acid synthesis and isoprenoid metabolism, metabolizing highly active carbonyls, and regulating retinal homeostasis in the tumor. Our preliminary data further indicate the importance of AKR1B10 in pancreatic carcinogenesis. 1) We have demonstrated that i) 23/36 (64%) pancreatic adenocarcinomas over-expressed AKR1B10 and 70% patients with AKR1B10 over-expression were smokers. AKR1B10 was over-expressed in early precancerous PanIN lesions and in mouse pancreatic carcinomas with mutant Kras allele. 2) Silencing AKR1B10 by siRNA in pancreatic carcinoma cells resulted in induction of apoptosis and inhibition of protein prenylation including Kras and HDJ2. 3) Diclofenac and Sulindac [non- steroidal anti-inflammatory drugs (NSAIDs)] are competitive inhibitors of AKR1B10. Our studies showed that diclofenac and sulindac inhibited AKR1B10 activity and reduced Kras protein prenylation in pancreatic carcinoma cells, and significantly inhibited pancreatic carcinogenesis and increased animal survival in the two genetically engineered mouse models of pancreatic cancers. 4) Transgenic flox-p AKR1B10fl/fl mice (AKR1B10fl/fl) and several powerful murine models of pancreatic carcinoma have been fully developed and well used in our lab. Our hypothesis is that knockout or inhibition of AKR1B10 will inhibit the development of pancreatic carcinoma, mechanistically through i) inhibiting activation of oncogenic Kras protein and other key prenylated proteins via metabolizing isoprenoids, ii) affecting carbonyl metabolism and/or iii) regulating retinal homeostasis in tumors. We will perform the following specific Aims to test this hypothesis: Aim 1: To determine the chemopreventive effects and mechanism of diclofenac on mutant Kras-driven and pancreatitis-enhanced carcinogenesis in Pdx1Cre-KrasG12D mice (called PanKras). Aim 2: To determine the role of AKR1B10 gene deficiency in pancreatic carcinogenesis using a most powerful mouse model of the tri-transgenic Pdx1Cre-KrasG12D-AKR1B10fl/fl mice (called PanKras/AKR1B10) that concurrently knockout AKR1B10 and activating KrasG12D allele in the pancreatic Pdx1+ progenitor cells. Aim 3: To determine the synergistic effect of retinol (vitamin A) and diclofenac on inhibiting pancreatic carcinogenesis in PanKras mice and to determine if the synergistic effect of vitamin A and diclofenac is via modulating retinal homeostasis in the tumor.

描述（由申请人提供）：该项目的目的是确定醛酮还原酶家族1成员B10 （AKR1B10）在胰腺癌发生中的作用，并建立使用强效AKR1B10抑制剂预防胰腺癌的有效策略。AKR1B10属于醛酮还原酶（AKR）家族，是一种独特的肿瘤生物标志物，在包括胰腺在内的吸烟相关癌中过表达。AKR1B10表现出比大多数人类AKR更有限的底物特异性：只有法尼醛、香叶基、视网膜和羰基是它的特异性底物。AKR1B10可以通过多种途径促进癌变，包括调节细胞脂肪酸合成和类异戊二烯代谢，代谢高活性羰基，调节肿瘤中视网膜稳态。我们的初步数据进一步表明AKR1B10在胰腺癌发生中的重要性。1)我们已经证明i) 23/36（64%）的胰腺腺癌过表达AKR1B10, 70%的AKR1B10过表达的患者是吸烟者。AKR1B10在早期癌前PanIN病变和Kras等位基因突变的小鼠胰腺癌中过表达。2)用siRNA沉默胰腺癌细胞中的AKR1B10，诱导细胞凋亡，抑制Kras和HDJ2等蛋白的烯酰化。3)双氯芬酸和舒林酸[非甾体抗炎药（NSAIDs）]是AKR1B10的竞争性抑制剂。我们的研究表明，双氯芬酸和舒林酸抑制胰腺癌细胞中AKR1B10活性，降低Kras蛋白戊烯化，显著抑制胰腺癌发生，提高两种胰腺癌基因工程小鼠模型的动物存活率。4)转基因flox-p AKR1B10fl/fl小鼠（AKR1B10fl/fl）和几种强大的胰腺癌小鼠模型已在本实验室得到充分开发和应用。我们的假设是，敲除或抑制AKR1B10将抑制胰腺癌的发展，其机制是通过i)通过代谢类异戊二烯抑制致癌Kras蛋白和其他关键的烯酰化蛋白的激活，ii)影响羰基代谢和/或iii)调节肿瘤中的视网膜稳态。我们将执行以下具体目的来验证这一假设：目的1：确定双氯芬酸对Pdx1Cre-KrasG12D小鼠（称为PanKras）突变型kras驱动和胰腺炎增强的癌变的化学预防作用和机制。目的2：利用最强大的三转基因Pdx1Cre-KrasG12D-AKR1B10fl/fl小鼠模型（称为PanKras/AKR1B10），同时敲除AKR1B10并激活胰腺Pdx1+祖细胞中的KrasG12D等位基因，确定AKR1B10基因缺陷在胰腺癌发生中的作用。目的3：确定视黄醇（维生素A）和双氯芬酸在抑制PanKras小鼠胰腺癌发生中的协同作用，并确定维生素A和双氯芬酸的协同作用是否通过调节肿瘤中的视网膜稳态来实现。