Cytosolic Ah Receptor: Mechanism of Action

胞质 Ah 受体：作用机制

• 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
• 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

 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)：芳香烃受体(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-对二恶英(TCDD)高亲和力结合的胞内蛋白，该受体还与结构相关的卤代芳烃和多核芳烃燃烧产物结合。TCDD的毒性机制已被深入研究，但尚未完全解决。随后一代的AhR基因敲除小鼠模型，再加上该受体与包括内源性生物化学物质、植物化学物质和药物在内的大量配体结合的发现，导致了显示AhR在细胞内稳态和包括癌症在内的多种疾病中的重要作用的发现。因此，研究AhR及其内源性和外源性配体及其作用机制对于了解该受体的不同功能是必不可少的。AhR作为一种配体激活的核转录因子的经典作用机制更为复杂，在某些细胞中，AhR在细胞核和胞浆中都是活跃的。本实验室的研究主要集中在内源性AhR配体和AhR活性药物的开发和作用机制上，这方面的应用主要集中在质子泵抑制剂奥美拉唑，它可以抑制高侵袭性的准间叶性胰腺导管癌细胞(QM-PDA)的侵袭。在Panc1细胞(一种QM-PDA细胞系)中，这种AhR依赖的抑制效应发生在没有配体诱导的AhR核摄取或诱导CyP1A1的情况下。我们假设一种新的胞内AhR途径介导了AhR活性药物对QM-PDA细胞侵袭的抑制作用，并将从以下两个方面探讨这种反应的机制。目的1重点介绍胞液和胞核AhR(AHRC和AhRn)在奥美拉唑等AhR活性药物抑制QM-PDA和经典胰腺癌细胞侵袭和迁移中的作用。AIM2将分析AHRC介导的胰腺癌细胞途径，并确定核进出口途径/运输和潜在的胞浆受体靶标的作用。这项拟议的研究将确定胰腺癌细胞中AHRC介导的新途径，该途径可能对不同细胞类型中该受体的其他功能也很重要。