文章：

靶向肝脏X受体的癌症治疗

Targeting liver X receptors in cancer therapeutics

原文发布日期：2015-03-19

DOI: 10.1038/nrc3912

类型: Review Article

开放获取: 否

要点：

1. Members of the nuclear receptor (NR) superfamily of ligand-dependent transcription factors have key roles in a number of cancers and are highly druggable targets.
2. Liver X receptors (LXRs) are NRs that function as oxysterol sensors in metabolic tissues and immune cells. Synthetic LXR ligands have been developed for the treatment of atherosclerosis.
3. LXRs are expressed in a variety of cancers, and treatment with synthetic ligands has been shown to block tumour cell proliferation, tumorigenesis and metastasis in multiple cancer models.
4. Mechanisms of action of LXR ligands in cancer models include alterations in the expression and function of cell cycle, signal transduction, hormone response, and metabolic genes and pathways, and LXR ligands target both tumour cells and immune and stromal cells in the tumour microenvironment.
5. The current generation of synthetic LXR ligands was developed for treating heart and metabolic diseases, and so these ligands have not been optimized for cancer-related end points. In addition to identifying novel cancer-targeting ligands, available tissue-specific and receptor subtype-specific ligands may be effective in treating certain responsive cancers.

要点翻译：

1. 核受体（NR）超家族作为配体依赖性转录因子，在多种癌症中发挥关键作用，且具有高度成药性。
2. 肝脏X受体（LXRs）是该家族成员，在代谢组织和免疫细胞中作为氧化甾醇传感器。人工合成的LXR配体已被开发用于治疗动脉粥样硬化。
3. LXRs在多种癌症中均有表达，研究显示合成配体处理在多个癌症模型中能抑制肿瘤细胞增殖、肿瘤发生及转移。
4. LXR配体在癌症模型中的作用机制包括改变细胞周期、信号转导、激素反应及相关代谢基因/通路的表达与功能，同时靶向肿瘤微环境中的肿瘤细胞、免疫细胞和基质细胞。
5. 当前开发的合成LXR配体旨在治疗心脏及代谢疾病，因此尚未针对癌症相关终点进行优化。除开发新型癌症靶向配体外，现有的组织特异性及受体亚型特异性配体或可有效治疗某些敏感型癌症。

英文摘要：

Members of the nuclear receptor superfamily of ligand-dependent transcription factors carry out vital cellular functions and are highly druggable therapeutic targets. Liver X receptors (LXRs) are nuclear receptor family members that function in cholesterol transport, glucose metabolism and the modulation of inflammatory responses. There is now accumulating evidence to support the involvement of LXRs in a variety of malignancies and the potential efficacy of their ligands in these diseases. This Review summarizes the discovery and characterization of LXRs and their ligands, their effects and mechanisms in preclinical cancer models, and the future directions of basic and translational LXR research in cancer therapeutics.

摘要翻译： 

核受体超家族成员作为配体依赖的转录因子，执行关键细胞功能，且为极具成药性的治疗靶点。肝X受体（LXRs）属核受体家族，参与胆固醇转运、葡萄糖代谢及炎症反应调控。越来越多证据表明，LXRs与多种恶性肿瘤相关，其配体在这些疾病中具有潜在疗效。本文综述LXRs及其配体的发现与表征、在临床前癌症模型中的作用与机制，以及LXR在癌症治疗中的基础与转化研究未来方向。

原文链接：

Targeting liver X receptors in cancer therapeutics