Identification of a novel class of retinoic acid receptor β-selective retinoid antagonists and their inhibitory effects on AP-1 activity and retinoic acid-induced apoptosis in human breast cancer cells
Identification of a novel class of retinoic acid receptor β-selective retinoid antagonists and their inhibitory effects on AP-1 activity and retinoic acid-induced apoptosis in human breast cancer cells
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DOI：
10.1074/jbc.274.22.15360
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发表时间：
1999-05-28
影响因子：
4.8
通讯作者：
Zhang, XK
中科院分区：
文献类型：
--
作者：
Li, Y;Hashimoto, Y;Zhang, XK
基于配体超家族的概念设计并合成了四种候选类维生素A拮抗剂（LE 135、LE 511、LE 540和LE 550）。通过瞬时转染分析这些相关的类维生素A，表明LE 135，LE 540和LE 550是有效的视黄酸受体（RAR）拮抗剂，而LE 511选择性诱导RAR β转录活性。LE 135和LE 540均抑制视黄酸（RA）诱导的RAR β的转录激活，但不抑制RAR α、RAR γ或类维生素A X受体α（RXR α）对多种RA应答元件的转录激活。类维生素A拮抗剂还抑制全反式RA诱导的RAR β/RXR α异二聚体的转录激活，尽管它们对RXR/ RXR同源二聚体的转录激活活性没有显示出任何影响。在ZR-75-1人乳腺癌细胞中，用全反式RA共处理LE 135和LE 540抑制了全反式RA诱导的细胞凋亡，进一步证明RAR β在RA诱导的乳腺癌细胞凋亡中起作用。我们还评估了这些类维生素A对AP-1活性的影响。我们的数据表明，LE 135和LE 540强烈抑制12-O-十四烷酰佛波醇-13-乙酸酯诱导的AP-1活性的RAR β和RXR α的存在下，有趣的是，LE 550诱导AP-1活性时，RAR β和RXR α表达在HeLa细胞，而不是在乳腺癌细胞。这些结果表明，LE 135和LE 540是一类新的RAR β选择性拮抗剂和抗AP-1类维甲酸，并应是有用的工具，用于研究类维甲酸及其受体的作用。
Four candidate retinoid antagonists (LE135, LE511, LE540, and LE550) were designed on the basis of the ligand superfamily concept and synthesized. Analysis of these related retinoids by transient transfection assay demonstrated that LE135, LE540, and LE550 are effective retinoic acid receptor (RAR) antagonists, whereas LE511 selectively induced RAR beta transcriptional activity. Both LE135 and LE540 inhibited retinoic acid (RA)induced transcriptional activation of RAR beta, but not RAR alpha, RAR gamma or retinoid X receptor alpha (RXR alpha), on a variety of RA response elements. The retinoid antagonists also inhibited all-trans-RA-induced transcriptional activation of RAR beta/RXR alpha heterodimers, although they did not show any effect on transactivation activity of RXR/ RXR homodimers, In ZR-75-1 human breast cancer cells, cotreatment of LE135 and LE540 with all-trans-RA inhibited all-trans-RA-induced apoptosis of the cells, further demonstrating that RAR beta plays a role in RA-induced apoptosis of breast cancer cells. We also evaluated the effect of these retinoids on AP-1 activity. Our data showed that LE135 and LE540 strongly repressed 12-O-tetradecanoylphorbol-13-acetate-induced AP-1 activity in the presence of RAR beta and RXR alpha, Interestingly, LE550 induced AP-1 activity when RAR beta and RXR alpha were expressed in HeLa cells but not in breast cancer cells. These results demonstrate that LE135 and LE540 were a novel class of RAR beta-selective antagonists and anti-AP-1 retinoids and should be useful tools for studying the role of retinoids and their receptors.