Graduate School of Biomedical Sciences, University of Texas Health Science Center at San Antonio, San Antonio, Texas.
Mol Carcinog. 2014 Jun;53(6):488-97. doi: 10.1002/mc.22002. Epub 2013 Jul 12.
Glucocorticoids (GCs) are very effective at preventing carcinogen- and tumor promoter-induced skin inflammation, hyperplasia, and mouse skin tumor formation. The effects of GCs are mediated by a well-known transcription factor, the glucocorticoid receptor (GR). GR acts via two different mechanisms: transcriptional regulation that requires DNA-binding (transactivation) and DNA binding-independent protein-protein interactions between GR and other transcription factors, such as nuclear factor kappa B (NF-κB) or activator protein 1 (AP-1; transrepression). We hypothesize that the transrepression activities of the GR are sufficient to suppress skin tumor promotion. We obtained two GCs (RU24858 and RU24782) that have dissociated downstream effects and induce only transrepression activities of the GR in a number of systems. These compounds bind the GR with high affinity and repress AP-1 and NF-κB activities while showing a lack of GR transactivation. RU24858, RU24782, or control full GCs desoximetasone (DES) and fluocinolone acetonide (FA) were applied to the dorsal skin of SENCAR mice prior to application of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), two times per week for 2 weeks. DES, FA and RU24858 reversed TPA-induced epidermal hyperplasia and proliferation, while RU24782 treatment had no effect on these markers of skin tumor promotion. All tested compounds decreased TPA-induced c-jun mRNA levels in skin. DES, FA, and RU24858, but not RU24782, were also able to reverse TPA-induced increases in the mRNA levels of COX-2 and iNOS. These findings show that RU24858 but not RU24782 reduced TPA-induced epidermal hyperplasia, proliferation, and inflammation, while both compounds reversed c-jun mRNA increases in the skin.
糖皮质激素（GCs）在预防致癌物和肿瘤促进剂引起的皮肤炎症、增生和小鼠皮肤肿瘤形成方面非常有效。GCs 的作用是通过一种众所周知的转录因子，即糖皮质激素受体（GR）介导的。GR 通过两种不同的机制发挥作用：需要 DNA 结合（转录激活）的转录调节和 GR 与其他转录因子（如核因子 kappa B（NF-κB）或激活蛋白 1（AP-1；转录抑制）之间的 DNA 结合非依赖性蛋白-蛋白相互作用。我们假设 GR 的转录抑制活性足以抑制皮肤肿瘤促进。我们获得了两种 GC（RU24858 和 RU24782），它们在许多系统中分离了下游效应，仅诱导 GR 的转录抑制活性。这些化合物与 GR 具有高亲和力，并抑制 AP-1 和 NF-κB 活性，同时显示缺乏 GR 转录激活。RU24858、RU24782 或对照全 GC 地塞米松（DES）和氟轻松丙酮（FA）在应用肿瘤促进剂 12-O-十四烷酰佛波醇-13-醋酸酯（TPA）之前应用于 SENCAR 小鼠的背部皮肤，每周两次，持续 2 周。DES、FA 和 RU24858 逆转了 TPA 诱导的表皮增生和增殖，而 RU24782 处理对这些皮肤肿瘤促进标志物没有影响。所有测试的化合物均降低了 TPA 诱导的皮肤 c-jun mRNA 水平。DES、FA 和 RU24858，但不是 RU24782，也能够逆转 TPA 诱导的 COX-2 和 iNOS mRNA 水平的增加。这些发现表明，RU24858 而不是 RU24782 减少了 TPA 诱导的表皮增生、增殖和炎症，而两种化合物均逆转了皮肤中 c-jun mRNA 的增加。
