Journal
PROSTATE
Volume 73, Issue 3, Pages 267-277Publisher
WILEY-BLACKWELL
DOI: 10.1002/pros.22566
Keywords
castration-resistant prostate cancer; AR-V7; PI3K
Categories
Funding
- VA Merit Review Program (Marcelli) [04H26-AB]
- DOD Prostate Cancer Res Program (Marcelli) [DAMD W81XWH-10-1-0390]
- South Central VA Health Care Network (VISN 16) Research Grant (Mediwala)
- Helis Foundation
- John S. Dunn Gulf Coast Consortium for Chemical Genomics [NIH 1F32DK85979]
- Diabetes & Endocrinology Research [P30 DK079638]
- BW O'Malley [SCCPR U54 HD-007495]
- MK Estes [P30 DK-56338]
- CK Osborne [P30 CA-125123]
- Dan L. Duncan Cancer Center of Baylor College of Medicine [DK-79638]
- Diana Helis Henry Medical Research Foundation
- Baylor College of Medicine
- Systems-Based Screening for Androgen Receptor Function Program
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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.
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