Cytosolic Ah Receptor: Mechanism of Action

胞质 Ah 受体：作用机制

基本信息

批准号：
9116193
负责人：
Stephen H. Safe
金额：
$ 18.12万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9116193
关键词：
ARNT gene ARNT protein Adenocarcinoma Cell Affinity Animal Model Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Autoimmune Diseases Binding Binding Proteins Biochemical Biological Markers CYP1A1 gene Cancer cell line Cell Line Cell Nucleus Cells Complex Coupled Cytosol Development Dioxins Disease Drug Targeting Gene Expression Gene Targeting Generations Health Homeostasis Immune Knock-out Knockout Mice Laboratories Ligands Malignant Neoplasms Malignant neoplasm of pancreas Mediating Nuclear Nuclear Export Nuclear Import Omeprazole Pancreatic Ductal Adenocarcinoma Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Phytochemical Play Proteins Proton Pump Inhibitors Recording of previous events Research Response Elements Role Tissues Toxic Environmental Substances Toxic effect Tryptophan Virulent Xenobiotics aryl hydrocarbon receptor ligand cancer cell cell type combustion product environmental chemical inhibitor/antagonist microbiota migration mouse model novel pancreatic cancer cells promoter receptor receptor binding receptor function response trafficking transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is a ligand-activated receptor that has an unusual history. The AhR was initially identified as the intracellular protein that bound the environmental toxicant 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) with high affinity, and the receptor also bound structurally-related halogenated aromatics and polynuclear aromatic hydrocarbon combustion products. The toxic mechanisms induced by TCDD have been studied in depth and have not yet been completely resolved. The subsequent generation of the AhR knockout mouse models coupled with the discovery that this receptor binds a vast array of ligands including endogenous biochemicals, phytochemicals and pharmaceuticals have led to discoveries showing the important roles of the AhR in cellular homeostasis and multiple diseases including cancer. Thus, research on the AhR and its endogenous and exogenous ligands and mechanisms of action are essential for understanding the diverse functions of this receptor. The classical mechanisms of action of the AhR as a ligand-activated nuclear transcription factor are more complex and, in some cells, the AhR is active in both the nucleus and cytosol. Research in this laboratory has focused on the development and mechanisms of action of endogenous AhR ligands and AhR-active pharmaceuticals, and this application is focused on the proton pump inhibitor omeprazole which inhibits invasion of highly aggressive quasimesenchymal pancreatic ductal adenocarcinoma (QM- PDA) cell types. This AhR-dependent inhibitory effect in Panc1 cells (a QM-PDA cell line) occurs in the absence of ligand-induced nuclear uptake of the AhR or the induction of CYP1A1, a well-characterized biomarker of Ah-responsiveness. We hypothesize that a novel cytosolic AhR pathway mediates the inhibition of QM-PDA cell invasion by AhR-active pharmaceuticals and the mechanism of this response will be investigated in the following two Aims. Aim 1 will focus on the role of the cytosolic and nuclear AhR (AhRc and AhRn) in mediating the inhibition of cancer cell invasion and migration of QM-PDA and classical pancreatic cancer cell lines treated with omeprazole and other AhR-active pharmaceuticals. Aim2 will analyze the AhRc-mediated pathway in pancreatic cancer cells and determine the roles of nuclear import and export pathways/trafficking and potential cytosolic targets of the receptor. The proposed studies will determine a novel AhRc-mediated pathway in pancreatic cancer cells that could also be important for other functions of the receptor in different cell types.

描述（由申请人提供）：芳烃受体（AhR）是一种配体激活的受体，具有不寻常的历史。AhR 最初被鉴定为与环境毒物 2,3,7,8-四氯二苯并- 结合的细胞内蛋白质。对二恶英（TCDD）具有高亲和力，并且该受体还与结构相关的卤代芳烃和多环芳烃燃烧产物结合。TCDD引起的毒性机制已被阐明。后续的 AhR 敲除小鼠模型的产生以及该受体结合大量配体（包括内源性生化物质、植物化学物质和药物）的发现，显示了该受体的重要作用。 AhR 在细胞稳态和包括癌症在内的多种疾病中的作用因此，对 AhR 及其内源性和外源性配体及其作用机制的研究对于了解该受体的多种功能至关重要。配体激活的核转录因子更为复杂，在某些细胞中，AhR 在细胞核和细胞质中均具有活性，该实验室的研究重点是内源性 AhR 配体和 AhR 活性药物的开发和作用机制。本申请的重点是质子泵抑制剂奥美拉唑，它可以抑制高度侵袭性的准间充质胰腺导管腺癌（QM-PDA）细胞类型的侵袭，这种AhR依赖性抑制作用。 Panc1 细胞（QM-PDA 细胞系）在没有配体诱导的 AhR 核摄取或 CYP1A1 诱导的情况下发生，CYP1A1 是 Ah 反应性的良好表征的生物标志物。 AhR 活性药物对 QM-PDA 细胞侵袭的影响以及这种反应的机制将在以下两个目标中进行研究。目标 1 将重点关注细胞质和细胞核的作用。 AhR（AhRc 和 AhRn）介导 QM-PDA 和经奥美拉唑和其他 AhR 活性药物治疗的经典胰腺癌细胞系的癌细胞侵袭和迁移抑制，Aim2 将分析胰腺癌细胞中 AhRc 介导的途径并确定。核输入和输出通路/转运的作用以及受体的潜在胞质靶点拟议的研究将确定胰腺癌细胞中的一种新的 AhRc 介导的通路。对于不同细胞类型中受体的其他功能很重要。