Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1
Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1
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DOI：
10.1124/mol.114.095554
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发表时间：
2015-02-01
影响因子：
3.6
通讯作者：
Griffin, Patrick R.
中科院分区：
文献类型：
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作者：
Corzo, Cesar A.;Mari, Yelenis;Griffin, Patrick R.
孤儿核受体肝受体同源物1（LRH-1; NR 5A 2）是胆固醇代谢和胆汁酸稳态的有效调节剂。最近，LRH-1已被证明在肠道炎症和雌激素受体阳性和阴性乳腺癌和胰腺癌的进展中发挥重要作用。结构研究表明，LRH-1可以结合磷脂和膳食磷脂二月桂酰磷脂酰胆碱激活LRH-1活性的啮齿动物。在这里，我们表征了一种新的合成LRH-1的非磷脂小分子阻遏物SR 1848（6-[4-（3-氯苯基）哌嗪-1-基]-3-环己基-1H-嘧啶-2，4-二酮）的活性。在共转染研究中，SR 1848降低了LRH-1依赖性报告基因的表达，并在内源性表达LRH-1的细胞中剂量依赖性地降低了细胞周期蛋白-D1和-E1的表达，从而抑制了细胞增殖。SR 1848处理的细胞效应在用靶向LRH-1的小干扰RNA转染细胞后重现。免疫细胞化学分析表明，SR 1848诱导核LRH-1快速易位到细胞质。结合，这些结果表明，SR 1848是LRH-1的功能性阻遏物，其影响参与表达LRH-1的癌症中增殖的基因的表达。因此，SR 1848代表了一种新的化学支架，用于开发靶向LRH-1驱动的恶性肿瘤的疗法。
The orphan nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2) is a potent regulator of cholesterol metabolism and bile acid homeostasis. Recently, LRH-1 has been shown to play an important role in intestinal inflammation and in the progression of estrogen receptor positive and negative breast cancers and pancreatic cancer. Structural studies have revealed that LRH-1 can bind phospholipids and the dietary phospholipid dilauroylphosphatidylcholine activates LRH-1 activity in rodents. Here we characterize the activity of a novel synthetic nonphospholipid small molecule repressor of LRH-1, SR1848 (6-[4-(3-chlorophenyl)piperazin-1-yl]-3-cyclohexyl-1H-pyrimidine-2,4-dione). In cotransfection studies, SR1848 reduced LRH-1-dependent expression of a reporter gene and in cells that endogenously express LRH-1 dose dependently reduced the expression of cyclin-D1 and -E1, resulting in inhibition of cell proliferation. The cellular effects of SR1848 treatment are recapitulated after transfection of cells with small-interfering RNA targeting LRH-1. Immunocytochemistry analysis shows that SR1848 induces rapid translocation of nuclear LRH-1 to the cytoplasm. Combined, these results suggest that SR1848 is a functional repressor of LRH-1 that impacts expression of genes involved in proliferation in LRH-1-expressing cancers. Thus, SR1848 represents a novel chemical scaffold for the development of therapies targeting malignancies driven by LRH-1.