Androgen mediated regulation and functional implications of FKBP51 expression in prostate cancer
Androgen mediated regulation and functional implications of FKBP51 expression in prostate cancer
复制标题
DOI：
10.1097/01.ju.0000155845.44729.ba
复制
发表时间：
2005-05-01
影响因子：
6.6
通讯作者：
Golub, TR
中科院分区：
文献类型：
--
作者：
Febbo, PG;Lowenberg, M;Golub, TR
目的：尽管生物活性雄激素受体（AR）靶基因仍然很大程度上未知，但雄激素消融仍然是转移性前列腺癌最有效的治疗方法。由于 AR 信号传导在激素难治性疾病中持续存在，因此效应 AR 靶基因可能具有治疗意义。 材料和方法：我们使用寡核苷酸微阵列来鉴定雄激素诱导表达并与雄激素非依赖性生长相关的基因。通过 Northern 和 Western 分析在 LNCaP 细胞中以及使用免疫组织化学在原发性前列腺样本中进一步研究了雄激素诱导的 FKBP51（一种类固醇受体伴侣）的表达。我们使用过表达 FKBP51 的稳定克隆来测试 FKBP51 的功能效果。结果：许多基因的表达与 LNCaP 细胞中的雄激素刺激相关，但相对较少的基因在多个前列腺癌细胞系中具有可重复的、雄激素介导的表达变化。 FYBP51在LNCaP细胞中具有雄激素诱导的RNA和蛋白质表达，并在去势后降低正常前列腺上皮细胞中的表达。进一 FKBP51 和 AR 之间的物理相互作用表明 FKBP51 过度表达会增加前列腺癌中的 AR 转录活性。
Purpose: Androgen ablation continues to be the most effective therapy for metastatic prostate cancer, although the biologically active androgen receptor (AR) target genes remain largely unknown. Because AR signaling continues in hormone refractory disease, effector AR target genes may have therapeutic import.Materials and Methods: We used oligonucleotide microarrays to identify genes with expression induced by androgen and associated with androgen independent growth. The androgen induced expression of FKBP51, a steroid receptor chaperone, was further investigated in LNCaP cells by Northern and Western analysis, and in primary prostate specimens using immunohistochemistry. We used stable clones over expressing FKBP51 to test the functional effects of FKBP51.Results: Many genes had expression that correlates with androgen stimulation in LNCaP cells but relatively few had reproducible, androgen mediated changes in expression across multiple prostate cancer cell lines. FYBP51 had androgen induced RNA and protein expression in LNCaP cells and decreased expression in normal prostate epithelial cells following castration. Further study demonstrated that FKBP51 induction was not a generalized response to cell proliferation, FKBP51 protein physically interacts with AR and LNCaP cells constitutively over expressing FKBP51 have increased ligand mediated AR activation of an exogenous AR reporter construct and endogenous prostate specific antigen.Conclusions: Taken together these results confirm FYBP51 as an androgen induced gene, demonstrate a physical interaction between FKBP51 and AR and suggest that FKBP51 over expression increases AR transcriptional activity in prostate cancer.