Complex impacts of PI3K/AKT inhibitors to androgen receptor gene expression in prostate cancer cells.

Liangliang Liu,Xuesen Dong,Irina U Agoulnik

doi:10.1371/journal.pone.0108780

Liangliang Liu, Xuesen Dong + Show 1 more

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https://doi.org/10.1371/journal.pone.0108780

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Journal: PloS one	Publication Date: Oct 31, 2014
Citations: 68	License type: CC BY 4.0

Affiliation: University of British Columbia, University of Toronto

Abstract

BackgroundAndrogen deprivation therapy (ADT) is the first-line treatment to metastatic prostate cancer (PCa). However, sustained expression and function of the androgen receptor (AR) gene contribute to the progression of castration resistant prostate cancers (CRPC). Additionally, tumors can adapt the PI3K/AKT survival pathway to escape ADT. Co-targeting AR and PI3K/AKT signaling has been proposed to be a more effective therapeutic means for CRPC patients. Many clinical trials are ongoing to test whether PI3K/AKT inhibitors are beneficial to PCa patients. However whether these inhibitors have any impacts on the expressions of full length AR (AR-FL) and its splice variant (AR-V7) remains unclear.MethodsFour human prostate cancer cell lines (LNCaP, LNCaP95, VCaP and 22Rv1) with different genetic backgrounds were treated with five PI3K/AKT inhibitors (LY294002, Wortmannin, BKM120, AKTi and AZD5363) and or AKT siRNA. AR and AR-V7 protein and mRNA levels were measured by immunoblotting and real-time PCR assays. AR gene transcription initiation, alternative RNA splicing and AR mRNA degradation rates were also determined.ResultsPI3K/AKT inhibitors had various impacts on AR protein expressions primarily through alterations of AR gene transcription initiation and RNA splicing. However, these effects remained unchanged in the presence RNA silencing of the AKT genes.ConclusionPI3K/AKT inhibitors have off-target effects on AR gene expression in prostate cancer cells, which shall be considered when applying these inhibitors to PCa patients, particularly patients under ADT treatment.

Highlights

Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer (PCa)
To determine the differences among experimental groups, one-way ANOVA followed by student t-test was carried out using GraphPad Prism with the level of significance set at P,0.05 as *, P,0.01 as ** and P,0.001 as ***
LY294002 repressed androgen receptor (AR)-FL protein levels in LNCaP cells (Fig. 1A), inhibited both AR-FL and AR-V7 protein levels in LNCaP95 cells (Fig. 1B). Both LNCaP and LNCaP95 cells are phosphatase and tensin homolog (PTEN) deficient cells, in which AKT is constitutively active in its phosphorylation form

Summary

Introduction

Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer (PCa). Several mechanisms have been proposed for aberrant AR re-activation post ADT including: i) AR gene amplification and gain-of-function mutations [4,6,7,8,9]; ii) alterations in expression and function of key AR co-regulators [10,11,12]; and iii) importantly, generation of ligand binding domain truncated AR splice variants (AR-Vs) [13,14,15,16] that constitutively activate the AR signaling. Whether these inhibitors have any impacts on the expressions of full length AR (AR-FL) and its splice variant (AR-V7) remains unclear

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