Restoration of FKBP51 protein promotes the progression of castration resistant prostate cancer.

Background: As deregulation of androgen receptor (AR) signaling target genes is associated with tumorigenesis and the development of prostate cancer (PCa), AR signaling is the primary therapeutic target for PCa. Although patients initially responses to first-line androgen deprivation therapies (ADTs), most of them with advanced PCa progress to lethal castration-resistant prostate cancer (CRPC). Recent studies have suggested the molecular mechanisms by which AR elicit the robust up-regulation of the gene. We suggest that restored expression of gene, modulated by androgen receptor splicing variant 7 (AR-V7) which replaces full length androgen receptor (AR-FL) in androgen ablation status, promotes CRPC progression through activating NF-κB signaling.

Methods: Immunohistochemistry assays were used to detect the expression of AR-V7, FKBP51 and NF-κB signaling correlated proteins in CRPC tissues. An androgen ablation resistant PCa cell line model established by Long-term culturing in androgen depleted medium, named androgen-independent LNCaP (LNCaP-AI) cells, were used to dynamically monitor FKBP51 expression during the process of androgen dependent PCa cells transforming into androgen-independent cells, as well as its association with NF-κB signal pathway. LNCaP-AI cell line was determined to express AR-V7 protein continuously. Luciferase reporter assays and DNA pull down were used to determine the association between AR-V7 and FKBP51.

Results: Our results suggested that CRPC patients with AR-V7 high expression tend to have higher expression of FKBP51 and enhanced NF-κB signaling compared with AR-V7 negative patients. Knockdown of AR-V7 or FKBP51 in LNCaP-AI cells attenuated the level of p-NF-κB (Ser536) and androgen-resistant cells growth. Luciferase reporter assays and DNA pull down results indicated that FKBP51 was transcriptionally promoted by AR-V7 in absence of androgen, which enhanced NF-κB signaling.

Conclusions: Because of upregulation of AR-V7 in androgen-independent PCa cells, increasing of FKBP51 induced NF-κB signaling, leading to progression of CRPC.