Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer
Molecular Pathways: The Role of NR4A Orphan Nuclear Receptors in Cancer
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DOI：
10.1158/1078-0432.ccr-11-2953
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发表时间：
2012-06-15
影响因子：
11.5
通讯作者：
Murphy, Evelyn P.
中科院分区：
文献类型：
--
作者：
Mohan, Helen M.;Aherne, Carol M.;Murphy, Evelyn P.
核受体在癌发生中具有不可或缺的重要性。经典的配体激活的核受体的操纵，如乳腺癌中的雌激素受体阻断，是一种重要的既定癌症治疗。孤儿核受体，如核家族4亚群A（NR 4A）受体，没有已知的天然配体。这些难以捉摸的受体越来越多地被认为是细胞存活的分子开关以及炎症和癌症之间的分子联系。NR 4A受体作为转录因子，改变凋亡（Fas-配体，TRAIL）、增殖、DNA修复、代谢、细胞迁移、炎症（白介素-8）和血管生成（VEGF）中下游基因的表达。NR 4A受体受多种细胞信号传导途径调节，包括蛋白激酶A/CREB、NF-κ B、磷酸肌醇3-激酶/AKT、c-jun-NH 2-激酶、Wnt和促分裂原活化蛋白激酶途径。NR 4A受体效应是环境和组织特异性的，受其表达水平、翻译后修饰以及与其他转录因子（RXR、PPAR-gamma）相互作用的影响。NR 4A“核受体”的亚细胞位置在功能上也是重要的;已经描述了NR 4A蛋白在细胞质中的新作用，其中NR 4A蛋白间接和直接作用于线粒体以通过Bcl-2促进凋亡。NR 4A受体涉及多种恶性肿瘤，包括乳腺癌、肺癌、结肠癌、膀胱癌和前列腺癌;多形性胶质母细胞瘤;肉瘤;和急性和/或慢性髓性白血病。NR 4A受体调节对常规化疗的反应，并代表了化疗干预的令人兴奋的前沿，因为现在已经开发出靶向NR 4A受体的新型药物。这篇综述提供了一个简明的临床概述目前的知识NR 4A信号在癌症和潜在的治疗操作。临床癌症研究; 18（12）; 3223-8。(C)2012年AACR。
Nuclear receptors are of integral importance in carcinogenesis. Manipulation of classic ligand-activated nuclear receptors, such as estrogen receptor blockade in breast cancer, is an important established cancer therapy. Orphan nuclear receptors, such as nuclear family 4 subgroup A (NR4A) receptors, have no known natural ligand(s). These elusive receptors are increasingly recognized as molecular switches in cell survival and a molecular link between inflammation and cancer. NR4A receptors act as transcription factors, altering expression of downstream genes in apoptosis (Fas-ligand, TRAIL), proliferation, DNA repair, metabolism, cell migration, inflammation (interleukin-8), and angiogenesis (VEGF). NR4A receptors are modulated by multiple cell-signaling pathways, including protein kinase A/CREB, NF-kappa B, phosphoinositide 3-kinase/AKT, c-jun-NH2-kinase, Wnt, and mitogen-activated protein kinase pathways. NR4A receptor effects are context and tissue specific, influenced by their levels of expression, posttranslational modification, and interaction with other transcription factors (RXR, PPAR-gamma). The subcellular location of NR4A "nuclear receptors" is also important functionally; novel roles have been described in the cytoplasm where NR4A proteins act both indirectly and directly on the mitochondria to promote apoptosis via Bcl-2. NR4A receptors are implicated in a wide variety of malignancies, including breast, lung, colon, bladder, and prostate cancer; glioblastoma multiforme; sarcoma; and acute and/or chronic myeloid leukemia. NR4A receptors modulate response to conventional chemotherapy and represent an exciting frontier for chemotherapeutic intervention, as novel agents targeting NR4A receptors have now been developed. This review provides a concise clinical overview of current knowledge of NR4A signaling in cancer and the potential for therapeutic manipulation. Clin Cancer Res; 18(12); 3223-8. (C) 2012 AACR.