Hembree J R, Agarwal C, Beard R L, Chandraratna R A, Eckert R
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970, USA.
Cancer Res. 1996 Apr 15;56(8):1794-9.
The hormones derived from vitamin A and related synthetic ligands (retinoids) are important regulators of differentiation and development and have been shown to be therapeutically useful in the treatment of cervical cancer. All-trans-retinoic acid exerts its effects by activation of retinoic acid receptor (RAR) and retinoid X receptor (RXR) heterodimers. These heterodimers bind to the retinoic acid response elements of target genes to regulate gene expression. RXR ligands act through RXR homodimers to regulate gene expression. In the present study, we describe the effects of RAR- and RXR-specific ligands on the regulation of insulin-like growth factor binding protein-3 (IGFBP-3) production and cell proliferation in human ectocervical epithelial (ECE) cell lines. Treatment of ECE16-1 cells with a RAR-specific ligand (TTNPB) or a ligand that interacts with both RAR and RXR receptors (9-cis-retinoic acid) increases IGFBP-3 levels and suppresses cell proliferation. In contrast, RXR-specific ligands (AGN191701, SR11217, and SR11237) do not regulate proliferation and slightly suppress the IGFBP-3 level. Cotreatment with increasing concentrations (0.01-1000nm) of RXR-specific ligand antagonizes the growth suppressive and IGFB-3-increasing effects of 1000 nM TTNPB. Similar results are observed in two other ECE cell lines, ECE16-D1 and ECE16-D2. These results indicate that RXR-specific ligands can antagonize RAR responses in these cell lines and suggest that a RAR-specific retinoid may be superior to one with mixed RAR/RXR binding activity for inhibiting cervical cancer cell proliferation. Moreover, the antagonism of RAR-dependent responses by RXR-specific ligands is consistent with a squelching model in which the RXR-specific ligand drives formation of RXR/RXR homodimers at the expense of the more active RAR/RXR heterodimers.
源自维生素A及相关合成配体（类视黄醇）的激素是分化和发育的重要调节因子，已被证明在宫颈癌治疗中具有治疗作用。全反式维甲酸通过激活维甲酸受体（RAR）和类视黄醇X受体（RXR）异二聚体发挥作用。这些异二聚体与靶基因的维甲酸反应元件结合以调节基因表达。RXR配体通过RXR同二聚体发挥作用来调节基因表达。在本研究中，我们描述了RAR和RXR特异性配体对人宫颈外上皮（ECE）细胞系中胰岛素样生长因子结合蛋白-3（IGFBP-3）产生和细胞增殖调节的影响。用RAR特异性配体（TTNPB）或与RAR和RXR受体均相互作用的配体（9-顺式维甲酸）处理ECE16-1细胞会增加IGFBP-3水平并抑制细胞增殖。相比之下，RXR特异性配体（AGN191701、SR11217和SR11237）不调节增殖，且轻微抑制IGFBP-3水平。用浓度递增（0.01 - 1000 nM）的RXR特异性配体共同处理可拮抗1000 nM TTNPB的生长抑制和IGFB-3增加作用。在另外两个ECE细胞系ECE16-D1和ECE16-D2中观察到类似结果。这些结果表明，RXR特异性配体可拮抗这些细胞系中的RAR反应，并提示RAR特异性类视黄醇在抑制宫颈癌细胞增殖方面可能优于具有混合RAR/RXR结合活性的类视黄醇。此外，RXR特异性配体对RAR依赖性反应的拮抗作用与一种抑制模型一致，即RXR特异性配体以更活跃的RAR/RXR异二聚体为代价驱动RXR/RXR同二聚体的形成。
