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最初被鉴定为以高亲和力结合环境毒物2,3,7,8-四氯二苯并-对二恶英（TCDD）的细胞内蛋白，该受体还结合结构相关的卤代芳烃和多核芳烃燃烧产物。 TCDD引起的毒性机制已被深入研究，但尚未完全解决。随后一代的 AhR 敲除小鼠模型，加上发现该受体与包括内源性生化物质、植物化学物质和药物在内的大量配体结合，这些发现表明了 AhR 在细胞稳态和包括癌症在内的多种疾病中的重要作用。因此，对 AhR 及其内源性和外源性配体以及作用机制的研究对于了解该受体的多种功能至关重要。 AhR 作为配体激活的核转录因子的经典作用机制更为复杂，并且在某些细胞中，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，本次应用的重点是质子泵抑制剂奥美拉唑，它能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。 Panc1 细胞（一种 QM-PDA 细胞系）中的这种 AhR 依赖性抑制作用是在没有配体诱导的 AhR 核摄取或 CYP1A1（一种充分表征的 Ah 反应性生物标志物）诱导的情况下发生的。我们假设一种新的胞质 AhR 途径介导 AhR 活性药物对 QM-PDA 细胞侵袭的抑制，并将在以下两个目标中研究这种反应的机制。 目标 1 将重点关注细胞质和细胞核 AhR（AhRc 和 AhRn）在介导用奥美拉唑和其他 AhR 活性药物治疗的 QM-PDA 和经典胰腺癌细胞系抑制癌细胞侵袭和迁移中的作用。 Aim2 将分析胰腺癌细胞中 AhRc 介导的通路，并确定核输入和输出通路/运输的作用以及受体的潜在胞质靶标。 拟议的研究将确定胰腺癌细胞中一种新的 AhRc 介导途径，该途径对于不同细胞类型中受体的其他功能也可能很重要。