The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way.
The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way.
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DOI：
10.1002/pros.22566
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发表时间：
2013-02-15
期刊：
影响因子：
2.8
通讯作者：
Marcelli, Marco
中科院分区：
文献类型：
--
作者：
Mediwala, Sanjay N.;Sun, Huiying;Szafran, Adam T.;Hartig, Sean M.;Sonpavde, Guru;Hayes, Teresa G.;Thiagarajan, Perumal;Mancini, Michael A.;Marcelli, Marco
雄激素受体 (AR) AR-V7 剪接亚型是一种组成型活性非法转录因子。前列腺癌向去势抵抗表型的转变与 AR-V7 积累相关，这表明传统治疗难治性患者的前列腺癌进展是由于这种 AR 亚型的活性。 AR-V7 组成型激活的机制尚不清楚。我们分析了 PTEN (−) PC-3 和 LNCaP 细胞中与 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、报告基因测定、RNAi 技术以及多种激酶抑制剂来确定 AR-V7 激活是否与激酶依赖性信号通路相关。在这些细胞系中，AR-V7 转录活性被 LY294002、Wortmanin 和 AKT 抑制剂 II 抑制。对影响机制的分析表明，磷脂酰肌醇 3 激酶 (PI3K)-AKT-FOXO1 信号通路参与其中，并且在 PTEN 重新激活的条件下 AR-V7 组成型活性显着降低。我们的研究确定了调节 AR-V7 组成活性的途径和治疗去势抵抗性前列腺癌的潜在治疗靶点。
The androgen receptor (AR) AR-V7 splice isoform is a constitutively active outlaw transcription factor. Transition of prostate cancer to the castration-resistant phenotype correlates with AR-V7 accumulation, suggesting that prostate cancer 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. 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. 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. Our study identifies a pathway regulating AR-V7 constitutive activity and potential therapeutic targets for the treatment of castration resistant prostate cancer.
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影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
4.1
作者：
Manin, M;Baron, S;Morel, L
通讯作者：
Morel, L
影响因子：
15
作者：
Kozikowski, AP;Sun, HY;Dennis, PA
通讯作者：
Dennis, PA
影响因子：
--
作者：
Ma, Qiuping;Fu, Wei;Bai, Wenlong
通讯作者：
Bai, Wenlong
DOI：
10.1016/j.bbapap.2007.10.003
发表时间：
2008-01-01
影响因子：
3.2
作者：
Marone, Romina;Cmijanovic, Vladimir;Wymann, Matthias P.
通讯作者：
Wymann, Matthias P.