Agarwal C, Chandraratna R A, Teng M, Nagpal S, Rorke E A, Eckert R L
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4970, USA.
Cell Growth Differ. 1996 Apr;7(4):521-30.
Retinoids are important regulators of human papillomavirus (HPV)-immortalized cervical epithelial cell differentiation and have been successfully used in the treatment of HPV-involved cervical cancer. In the present study, we examine the effects of a series of natural and synthetic retinoids on differentiation and proliferation of HPV-16-positive lines, ECE16-1 and CaSki. Retinoic acid receptor alpha (RAR alpha), RAR gamma, and retinoid X receptor alpha (RXR alpha) are the major retinoid receptor subtypes expressed when ECE16-1 cells are grown in retinoid-free medium. Our results indicate that ligands that interact with RARs only or both RARs and RXRs, including all-trans-retinoic acid (all-trans-RA), 9-cis-retinoic acid (9-cis-RA), 13-cis-retinoic acid (13-cis-RA), and several synthetic retinoids, suppress ECE16-1 cell proliferation, regulate expression of the retinoid-responsive differentiation marker cytokeratin K5, and increase RAR beta mRNA levels. In contrast, ligands that specifically interact with RXRs do not suppress proliferation and are less efficient regulators of gene expression. CaSki cells express greatly reduced RAR and RXR levels compared to ECE16-1 cells. However, both RAR- and RXR-specific ligands increase CaSki number by > or = 20%. In addition, RXR-specific ligands suppress cytokeratin K5 mRNA levels slightly, compared to RAR-specific ligands that strongly suppress K5 mRNA levels. We also compare the effects of these agents on the proliferation of other cervical cell lines, including ECE16-D2, ME180, and SiHa cells. ECE16-D2 and ME180 cells are growth suppressed by RAR-specific, but not RXR-specific, retinoids. SiHa cells are not responsive to either class of retinoid. Our results indicate that: (a) the response of different human cervical cell lines varies following treatment with receptor type-specific retinoids; and (b) the relationship between retinoid regulation of proliferation and differentiation can be uncoupled.
维甲酸是人类乳头瘤病毒（HPV）永生化宫颈上皮细胞分化的重要调节因子，并已成功用于治疗HPV相关的宫颈癌。在本研究中，我们检测了一系列天然和合成维甲酸对HPV - 16阳性细胞系ECE16 - 1和CaSki分化及增殖的影响。当ECE16 - 1细胞在无维甲酸培养基中生长时，维甲酸受体α（RARα）、RARγ和维甲酸X受体α（RXRα）是主要表达的维甲酸受体亚型。我们的结果表明，仅与RARs相互作用或同时与RARs和RXRs相互作用的配体，包括全反式维甲酸（all - trans - RA）、9 - 顺式维甲酸（9 - cis - RA）、13 - 顺式维甲酸（13 - cis - RA）以及几种合成维甲酸，可抑制ECE16 - 1细胞增殖，调节维甲酸反应性分化标志物细胞角蛋白K5的表达，并增加RARβ mRNA水平。相比之下，特异性与RXRs相互作用的配体不抑制增殖，且对基因表达的调节效率较低。与ECE16 - 1细胞相比，CaSki细胞中RAR和RXR水平大幅降低。然而，RAR特异性和RXR特异性配体均使CaSki细胞数量增加≥20%。此外，与强烈抑制K5 mRNA水平的RAR特异性配体相比，RXR特异性配体对细胞角蛋白K5 mRNA水平的抑制作用较弱。我们还比较了这些药物对其他宫颈细胞系增殖的影响，包括ECE16 - D2、ME180和SiHa细胞。ECE16 - D2和ME180细胞的生长受到RAR特异性而非RXR特异性维甲酸的抑制。SiHa细胞对这两类维甲酸均无反应。我们的结果表明：（a）用受体类型特异性维甲酸处理后，不同人类宫颈细胞系的反应有所不同；（b）维甲酸对增殖和分化的调节关系可能会解偶联。
