Abstract
The androgen receptor (AR) plays a central role in prostate, muscle, bone and adipose tissue. Moreover, dysregulated AR activity is a driving force in prostate cancer (PCa) initiation and progression. Consequently, antagonizing AR signalling cascades via antiandrogenic therapy is a crucial treatment option in PCa management. Besides, very high androgen levels also inhibit PCa cells’ growth, so this effect could also be applied in PCa therapy. However, on the molecular and cellular level, these mechanisms have hardly been investigated so far. Therefore, the present study describes the effects of varying androgen concentrations on the viability of PCa cells as well as localization, transactivation, and protein stability of the AR. For this purpose, cell viability was determined via WST1 assay. Alterations in AR transactivity were detected by qPCR analysis of AR target genes. A fluorescent AR fusion protein was used to analyse AR localization microscopically. Changes in AR protein expression were detected by Western blot. Our results showed that high androgen concentrations reduce the cell viability in LNCaP and C4-2 cell lines. In addition, androgens have been reported to increase AR transactivity, AR localization, and AR protein expression levels. However, high androgen levels did not reduce these parameters. Furthermore, this study revealed an androgen-induced increase in AR protein synthesis. In conclusion, inhibitory effects on cell viability by high androgen levels are due to AR downstream signalling or non-genomic AR activity. Moreover, hormonal activation of the AR leads to a self-induced stabilization of the receptor, resulting in increased AR activity. Therefore, in clinical use, a therapeutic reduction in androgen levels represents a clinical target and would lead to a decrease in AR activity and, thus, AR-driven PCa progression.
Highlights
The androgen receptor (AR), known as NR3C4, is coded by the AR gene on the X chromosome (Xq11-12) [1]
It is suggested that the biphasic effect is partially explained by the influence of R1881 concentrations on coactivators influencing the transcriptional activity of nuclear receptors [33,44]
The influence of low and high R1881 concentrations on the AR target genes PSA, TMPRSS2, and PROSTEIN was assessed. Both tested cell lines showed a concentration-dependent increase of the three AR target genes PSA, TMPRSS2, and PROSTEIN, reaching a plateau at 1 nM R1881
Summary
The androgen receptor (AR), known as NR3C4, is coded by the AR gene on the X chromosome (Xq11-12) [1]. The protein belongs to the nuclear receptor superfamily and is activated by binding androgenic hormones, including testosterone and dihydrotestosterone (DHT) [2,3]. The AR protein structure is similar to other nuclear receptors [6,7,8] It consists of eight exons sequentially coding the N-terminal transactivation domain, the DNA-binding domain, the hinge region, and the ligand-binding domain [6,7,8]. DHT-mediated activation of the AR causes a conformational change where the AR dimerizes, which triggers AR nuclear translocation, followed by binding to androgen response elements (ARE) of the DNA. Coregulators mediate the AR’s ability to transactivate the target gene, such as the prostate-specific antigen (PSA, known as Kallikrein 3) or the transmembrane serine protease (TMPRSS2) through chromatin remodelling and basal transcriptional machinery recruitment [11,12,13]. Genes regulated by the AR modify protein folding, trafficking and secretion, cell cycle, metabolism, biosynthetic pathways, and regulation of several transcription factors [13]
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