Yemelyanov A, Czwornog J, Chebotaev D, Karseladze A, Kulevitch E, Yang X, Budunova I
Department of Dermatology, Feinberg Medical School, Northwestern University, Chicago, IL 60611, USA.
Oncogene. 2007 Mar 22;26(13):1885-96. doi: 10.1038/sj.onc.1209991. Epub 2006 Oct 2.
Glucocorticoids are extensively used in combination chemotherapy of advanced prostate cancer (PC). Little is known, however, about the status of the glucocorticoid receptor (GR) in PC. We evaluated over 200 prostate samples and determined that GR expression was strongly decreased or absent in 70-85% of PC. Similar to PC tumors, some PC cell lines, including LNCaP, also lack GR. To understand the role of GR, we reconstituted its expression in LNCaP cells using lentiviral approach. Treatment of LNCaP-GR cells with the glucocorticoids strongly inhibited proliferation in the monolayer cultures and blocked anchorage-independent growth. This was accompanied by upregulation of p21 and p27, down-regulation of cyclin D1 expression and c-Myc phosphorylation. Importantly, the activation of GR resulted in normalized expression of PC markers hepsin, AMACR, and maspin. On the signaling level, GR decreased expression and inhibited activity of the MAP-kinases (MAPKs) including p38, JNK/SAPK, Mek1/2 and Erk1/2. We also found that activation of GR inhibited activity of numerous transcription factors (TF) including AP-1, SRF, NF-kappaB, p53, ATF-2, CEBPalpha, Ets-1, Elk-1, STAT1 and others, many of which are regulated via MAPK cascade. The structural analysis of hepsin and AMACR promoters provided the mechanistic rationale for PC marker downregulation by glucocorticoids via inhibition of specific TFs. Our data suggest that GR functions as a tumor suppressor in prostate, and inhibits multiple signaling pathways and transcriptional factors involved in proliferation and transformation.
糖皮质激素被广泛应用于晚期前列腺癌（PC）的联合化疗。然而，关于糖皮质激素受体（GR）在前列腺癌中的状态却知之甚少。我们评估了200多个前列腺样本，确定在70 - 85%的前列腺癌中GR表达强烈降低或缺失。与前列腺癌肿瘤相似，一些前列腺癌细胞系，包括LNCaP，也缺乏GR。为了了解GR的作用，我们采用慢病毒方法在LNCaP细胞中重建其表达。用糖皮质激素处理LNCaP - GR细胞强烈抑制单层培养中的增殖，并阻断非锚定依赖性生长。这伴随着p21和p27的上调、细胞周期蛋白D1表达的下调以及c - Myc磷酸化。重要的是，GR的激活导致前列腺癌标志物hepsin、AMACR和maspin的表达正常化。在信号传导水平上，GR降低了包括p38、JNK/SAPK、Mek1/2和Erk1/2在内的丝裂原活化蛋白激酶（MAPK）的表达并抑制其活性。我们还发现GR的激活抑制了众多转录因子（TF）的活性，包括AP - 1、SRF、NF - κB、p53、ATF - 2、CEBPα、Ets - 1、Elk - 1、STAT1等，其中许多是通过MAPK级联反应调控的。hepsin和AMACR启动子的结构分析为糖皮质激素通过抑制特定转录因子下调前列腺癌标志物提供了机制依据。我们的数据表明，GR在前列腺中起肿瘤抑制作用，并抑制参与增殖和转化的多种信号通路和转录因子。
