The androgen receptor (AR) plays a major role in driving prostate cancer (PCa). However, despite the use of AR inhibitors, intrinsic and non-genomic AR activation develops in many PCa patients, leading to metastatic, castration-resistant PCa (CRPC). This presents a major clinical problem, with no current therapies being able to effectively overcome CRPC progression. The metastasis suppressor N-myc down-stream regulated gene 1 (NDRG1) is negatively correlated with PCa progression, being able to inhibit multiple signalling pathways that drive PCa metastasis. However, its interaction with the key driver of PCa, namely AR, has never been assessed and was the major aim of this study. Further, the novel clinically-trialled anti-cancer agent DpC, which up-regulates NDRG1, was also examined for its potential against both androgen-dependent and independent PCa in vitro and in vivo.
We examined how NDRG1 expression affects genomic and non-genomic AR signalling networks in both androgen-dependent (LNCaP) and androgen-independent (C4-2B) PCa cells in response to testosterone (genomic) and EGF (non-genomic) stimulation using both 2D and 3D tissue culture models. We also assessed the novel agent DpC and its potential to inhibit AR signalling in vitro and in vivo, comparing it to the current “gold-standard” for CRPC, Enzalutamide.
We discovered that NDRG1 plays a major role in both genomic and non-genomic AR activation. These effects were mediated by its unique ability to: (i) directly stabilize the AR-HSP70/90 complex, preventing AR activation in response to testosterone; (ii) prevent non-genomic EGF-mediated activation of AR via inhibition of PI3K/AKT, JAK/STAT and MAPK pathways, and; (iii) inhibit activation of major co-factors that promote AR transcriptional activity (i.e. c-Jun). Importantly, targeting NDRG1 using DpC had similar effects, leading to marked inhibition of genomic and non-genomic AR activation and its down-stream signalling in vitro and in vivo. In fact, DpC potently reduced PCa tumour growth, AR and PSA levels in vivo, being more effective than the currently used treatment, Enzalutamide.