NUCLEAR RECEPTOR LIGAND TARGETING BY THE FATTY ACID BINDING PROTEINS: IMPLICATION

脂肪酸结合蛋白靶向核受体配体：意义

• 批准号: 8554750
• 负责人: Mary Kathryn Doud
• 金额: $ 4.22万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8554750
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Affinity; Anticarcinogenic Agents; Apoptosis; Apoptotic; Behavior; Binding; Binding Proteins; Cancer Cell Growth; Cell Cycle Arrest; Cell Proliferation; Cell Survival; Cells; Chemopreventive Agent; Clinical; Data; Development; Equilibrium; Fatty Acids; Gene Expression; Genes; Goals; Growth; Hormones; Human; Inhibition of Cancer Cell Growth; Lead; Ligands; Lipid Binding; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Modeling; Nuclear Receptors; PPAR delta; Pathway interactions; Proteins; Research; Resistance; Retinoic Acid Receptor; Retinoids; Series; Signal Transduction; Stearates; Testing; Therapeutic Agents; Tretinoin; Up-Regulation; Vitamin A; Work; base; cancer cell; cancer therapy; cell growth; cellular retinoic acid binding protein II; fatty acid-binding proteins; high throughput screening; human FABP5 protein; inhibitor/antagonist; insight; novel; oncology; pre-clinical; receptor; response; small molecule; transcription factor; tumor; tumor growth; tumorigenesis

Retinoic acid (RA) is a potent anticarcinogenic agent that functions by regulating the expression of multiple genes through its ability to activate two transcription factors: RAR and PPARDELTA. However, its utility as a therapeutic agent is limited by RA-resistance that is acquired in some tumors. Activation of RAR results in inhibition of cancer cell growth, while activation of PPARDELTA leads to enhanced growth and survival. The key to regulating the partitioning of RA between these two opposing pathways lies in the two proteins that deliver RA to their respective transcription factors: CRABP-II, which delivers RA to RAR, and FABP5, which transports it to PPARDELTA. Hence, cells that express a high level of FABP5 become resistant to RA-induced growth inhibition and, instead, display enhanced proliferation in response to RA. The goal of this work is to further investigate this partitioning between RAR and PPARDELTA using naturally occurring retinoids and fatty acids as probes. Moreover, this projects aims to develop a small molecule inhibitor(s) for FABP5 which could ultimately yield a novel class of anticarcinogenic molecules to synergize with RA.

维甲酸(RA)是一种有效的抗癌药物，它通过激活RAR和PPARDELTA两个转录因子来调节多个基因的表达。然而，它作为一种治疗剂的有效性受到一些肿瘤获得性RA耐药性的限制。RAR的激活抑制了癌细胞的生长，而PPARDELTA的激活则促进了癌细胞的生长和存活。调节RA在这两条相反途径之间分配的关键在于两种蛋白质：CRABP-II和FABP5，这两种蛋白质将RA运送到各自的转录因子：CRABP-II将RA运送到RAR，FABP5将RA运送到PPARDELTA。因此，高水平表达FABP5的细胞对RA诱导的生长抑制具有抵抗力，相反，对RA表现出促进增殖的反应。这项工作的目标是进一步研究RAR和PPARDELTA之间的这种分配，使用自然产生的维甲酸和脂肪酸作为探针。此外，该项目旨在开发FABP5的小分子抑制剂(S)，最终可能产生一类与RA协同作用的新型抗癌分子。