The activity of the androgen receptor variant AR-V7 is regulated by FOXO1 in a PTEN-PI3K-AKT-dependent way

被引：49
作者：
Mediwala, Sanjay N. [1 ,2 ]
Sun, Huiying [1 ,2 ]
Szafran, Adam T. [3 ]
Hartig, Sean M. [3 ]
Sonpavde, Guru [1 ,2 ]
Hayes, Teresa G. [1 ,2 ]
Thiagarajan, Perumal [2 ,4 ]
Mancini, Michael A. [3 ]
Marcelli, Marco [1 ,2 ,3 ]
机构：
[1] Baylor Coll Med, Dept Med, Houston, TX 77030 USA
[2] Michael E DeBakey VA Med Ctr, Dept Med, Houston, TX USA
[3] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA
来源：
PROSTATE | 2013年 / 73卷 / 03期
关键词：
castration-resistant prostate cancer; AR-V7; PI3K; PROSTATE-CANCER CELLS; SIGNALING PATHWAY; PTEN EXPRESSION; PHOSPHOINOSITIDE; 3-KINASE; FREQUENT INACTIVATION; SPLICE VARIANTS; MOUSE MODEL; ACTIVATION; AKT; THERAPY;
D O I：
10.1002/pros.22566
中图分类号：
R5 [内科学];
学科分类号：
1002 ; 100201 ;
摘要：
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. Prostate 73: 267277, 2013. (c) 2012 Wiley Periodicals, Inc.
引用
收藏
页码：267 / 277
页数：11
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