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The Activity of the Androgen Receptor Variant AR-V7 Is Regulated by FOXO1 in a PTEN-PI3K-AKT-dependent Way

Sanjay N Mediwala, Huiying Sun, Adam T Szafran, Sean M Hartig, Guru Sonpavde, Teresa G Hayes, Perumal Thiagarajan, Michael A Mancini, Marco Marcelli

Prostate. 2013 Feb 15;73(3):267-77.

PMID: 22821817

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
IAR42415211 Akt Inhibitor II Akt Inhibitor II Price
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