The three-orphan nuclear receptor 4A genes are induced by diverse stressors and stimuli, and there is increasing evidence that NR4A1 (Nur77), NR4A2 (Nurr1) and NR4A3 (Nor1) play an important role in maintaining cellular homeostasis and in pathophysiology. In blood-derived tumors (leukemias and lymphomas) NR4A expression is low and NR4A1-/-/NR4A3-/- double knockout mice rapidly develop acute myelocytic leukemia suggesting that these receptors exhibit tumor suppressor activity. Treatment of leukemia and most lymphoma cells with drugs that induce expression of NR4A1and NR4A3 enhances apoptosis and this represents a potential clinical application for treating this disease. In contrast, most solid tumor-derived cell lines express high levels of NR4A1 and NR4A2 and both receptors exhibit pro-oncogenic activities in solid tumors whereas NR4A3 exhibits tumor-specific activities. Initial studies with retinoids and apoptosis-inducing agents demonstrated that their cytotoxic activity is NR4A1-dependent and involved drug-induced nuclear export of NR4A1 and formation of a mitochondrial pro-apoptotic NR4A1- bcl-2 complex. Drug-induced nuclear export of NR4A1 has been reported for many agents/biologics and involves interactions with multiple mitochondrial and extramitochondrial factors to induce apoptosis. Synthetic ligands for NR4A1, NR4A2 and NR4A3 have been identified and among these compounds bis-indole derived (CDIM) NR4A1 ligands primarily act on nuclear NR4A1 to inhibit NR4A1-regulated pro-oncogenic pathways/genes and similar results have been observed for CDIMs that bind NR4A2. Based on results of laboratory animal studies development of NR4A inducers (blood-derived cancers) and NR4A1/NR4A2 antagonists (solid tumors) may be promising for cancer therapy and also for enhancing immune surveillance.

中文翻译：

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孤儿核受体 4A (NR4A) 在癌症中的矛盾作用

三孤核受体 4A 基因由多种应激源和刺激物诱导，越来越多的证据表明 NR4A1 (Nur77)、NR4A2 (Nurr1) 和 NR4A3 (Nor1) 在维持细胞稳态和病理生理学中起重要作用。在血源性肿瘤（白血病和淋巴瘤）中，NR4A 表达低，NR4A1-/-/NR4A3-/- 双敲除小鼠迅速发展为急性髓细胞性白血病，表明这些受体表现出肿瘤抑制活性。用诱导 NR4A1 和 NR4A3 表达的药物治疗白血病和大多数淋巴瘤细胞可增强细胞凋亡，这代表了治疗这种疾病的潜在临床应用。相比之下，大多数实体瘤来源的细胞系表达高水平的 NR4A1 和 NR4A2，这两种受体在实体瘤中都表现出促癌活性，而 NR4A3 表现出肿瘤特异性活性。对类视黄醇和凋亡诱导剂的初步研究表明，它们的细胞毒活性是 NR4A1 依赖性的，并且涉及药物诱导的 NR4A1 核输出和线粒体促凋亡 NR4A1-bcl-2 复合物的形成。已经报道了许多药物/生物制剂的药物诱导的 NR4A1 核输出，并且涉及与多种线粒体和线粒体外因子的相互作用以诱导细胞凋亡。NR4A1 的合成配体，NR4A2 和 NR4A3 已被鉴定，在这些化合物中，双吲哚衍生 (CDIM) NR4A1 配体主要作用于核 NR4A1 以抑制 NR4A1 调节的促致癌途径/基因，并且对于结合 NR4A2 的 CDIM 也观察到了类似的结果。根据实验室动物研究的结果，开发 NR4A 诱导剂（血源性癌症）和 NR4A1/NR4A2 拮抗剂（实体瘤）可能有望用于癌症治疗以及增强免疫监视。