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

基本信息

批准号：
8220421
负责人：
Guang-Yu Yang
金额：
$ 33.1万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
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/8220421
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

项目摘要

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. PUBLIC HEALTH RELEVANCE: Smoking and chronic pancreatitis are the most clearly established risk factors for the development of pancreatic cancer. Chronic pancreatitis leads to malabsorption and nutritional deficiency, particularly of fat-soluble vitamins including vitamin A. AKR1B10 is a unique tumor biomarker that is over-expressed in smoking related carcinomas such as pancreas and is involved in down-regulation of anti-neoplastic retinoic acid. Therefore, the importance of this project is to develop a new and efficient strategy for the prevention of highly lethal pancreatic cancer through targeting AKR1B10.

描述（由申请人提供）：该项目的目的是确定Aldo-Keto还原酶家族1成员B10（AKR1B10）在胰腺癌中的作用，并建立有效的AKR1B10抑制剂来预防胰腺癌的有效策略。 AKR1B10属于Aldo-Keto还原酶（AKR）家族，是一种独特的肿瘤生物标志物，在包括胰腺在内的与吸烟相关的癌中过表达。与大多数人AKR相比，AKR1B10的底物特异性更受限制的底物特异性：只有Farnesal，Geranylgeranial，视网膜和羰基是其特定的底物。 AKR1B10可以通过多种方式促进癌变，包括调节细胞脂肪酸合成和异普尼代谢，代谢高度活性的羰基，并调节肿瘤中的视网膜稳态。我们的初步数据进一步表明了AKR1B10在胰腺癌发生中的重要性。 1）我们已经证明，i）23/36（64％）胰腺腺癌过度表达的AKR1B10和70％AKR1B10过表达的患者是吸烟者。 AKR1B10在早期的癌前病变和带有突变体Kras等位基因的小鼠胰腺癌中过表达。 2）siRNA在胰腺癌细胞中通过siRNA沉默的AKR1B10导致诱导凋亡和抑制包括KRAS和HDJ2在内的蛋白质原始化。 3）双氯芬酸和硫酸[非类固醇抗炎药（NSAIDS）]是AKR1B10的竞争抑制剂。我们的研究表明，双氯芬酸和硫酸菌抑制了胰腺癌细胞中的AKR1B10活性，并降低了KRAS蛋白原始化，并显着抑制了胰腺癌的两种基因工程小鼠模型的胰腺癌的生存，并增加了动物生存。 4）转基因Flox-P AKR1B10FL/FL小鼠（AKR1B10FL/FL）和几种强大的胰腺癌模型已在我们的实验室中得到充分开发和充分使用。我们的假设是，AKR1B10的敲除或抑制将抑制胰腺癌的发展，从机械上i）通过i）抑制致癌性KRAS蛋白的激活，而其他关键的原蛋白蛋白质和其他代谢蛋白质通过代谢性异型类异丙也是如此肿瘤。我们将执行以下特定目的来检验这一假设：目的1：确定双氯芬酸对突变体KRAS驱动和胰腺炎增强的癌变的化学预防作用和机制。 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+祖细胞。 AIM 3：确定视黄醇（维生素A）和双氯芬酸对抑制pancreatic癌的协同作用，并确定维生素A和双氯芬酸是否通过肿瘤中的稳态调节性稳态来确定维生素A和双氯芬酸的协同作用。公共卫生相关性：吸烟和慢性胰腺炎是胰腺癌发展最清晰的危险因素。慢性胰腺炎会导致吸收不良和营养缺乏，特别是包括维生素A的脂溶性维生素A。AKR1B10是一种独特的肿瘤生物标记物，在吸烟相关的癌（例如胰腺）中过度表达，例如胰腺，并且参与了抗毒酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性酸性乙酸。因此，该项目的重要性是通过针对AKR1B10制定一种预防高度致命的胰腺癌的新策略。