雄激素受体变体 AR-V7 的活性受到 FOXO1 的调控，这种调控方式依赖于 PTEN-PI3K-AKT。
The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way.
机构信息
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
出版信息
Prostate. 2013 Feb 15;73(3):267-77. doi: 10.1002/pros.22566. Epub 2012 Jul 20.
BACKGROUND
The androgen receptor (AR) AR-V7 splice isoform is a constitutively active outlaw transcription factor. Transition of prostate cancer (PC) to the castration-resistant phenotype correlates with AR-V7 accumulation, suggesting that PC progression in patients refractory to conventional therapy is due to the activity of this AR isoform. The mechanism of AR-V7 constitutive activation is not known.
METHODS
We analyzed potential signaling pathways associated with AR-V7 constitutive activation in PTEN (-) PC-3 and LNCaP cells. We used transient and stable transfection, reporter gene assay, RNAi technology together with a number of kinase inhibitors to determine if AR-V7 activation is linked to a kinase-dependent signaling pathway.
RESULTS
In these cell lines, AR-V7 transcriptional activity was inhibited by LY294002, Wortmanin, and AKT inhibitor II. Analysis of the contributing mechanisms demonstrated the involvement of the Phosphatidylinositol 3-kinase (PI3K)-AKT-FOXO1 signaling pathway, and a significant reduction of AR-V7 constitutive activity under conditions of PTEN reactivation.
CONCLUSIONS
Our study identifies a pathway regulating AR-V7 constitutive activity and potential therapeutic targets for the treatment of castration-resistant PC.
背景
雄激素受体 (AR) AR-V7 剪接异构体是一种组成型激活的非法转录因子。前列腺癌 (PC) 向去势抵抗表型的转变与 AR-V7 的积累相关，这表明在对常规治疗有抗药性的患者中，PC 的进展是由于这种 AR 异构体的活性。AR-V7 组成型激活的机制尚不清楚。
方法
我们分析了与 PTEN(-)PC-3 和 LNCaP 细胞中 AR-V7 组成型激活相关的潜在信号通路。我们使用瞬时和稳定转染、报告基因检测、RNAi 技术以及多种激酶抑制剂来确定 AR-V7 的激活是否与依赖激酶的信号通路有关。
结果
在这些细胞系中，LY294002、Wortmanin 和 AKT 抑制剂 II 抑制了 AR-V7 的转录活性。对促成机制的分析表明，磷酸肌醇 3-激酶 (PI3K)-AKT-FOXO1 信号通路的参与，以及在 PTEN 重新激活的条件下，AR-V7 组成型活性的显著降低。
结论
我们的研究确定了调节 AR-V7 组成型活性的途径，并为治疗去势抵抗性 PC 提供了潜在的治疗靶点。
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