Abstract
A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin (IL)-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT1 receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.
Highlights
Worldwide, prostate cancer is the fourth most common human cancer and the second most common cancer in men [1]
Given that androgen receptor splice variant-7 (AR-V7) expression increases in castration-resistant prostate cancer (CRPC) xenografts treated with enzalutamide or abiraterone [13,14] and that detection of androgen receptor (AR)-V7 in circulating tumor cells from patients with CRPC may be associated with resistance to enzalutamide or abiraterone [15], constitutively active AR-V7 and related androgen receptor splice variants (AR-Vs) are likely to play a dominant role in inducing resistance to abiraterone and enzalutamide
We demonstrated that transient ectopic AR-V7 overexpression in LNCaP and 22Rv1 prostate cancer cells activate NF-κB with a resultant increase in IL-6 gene expression (Figures 3–5)
Summary
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