Aim: 

Prostate cancer is one of the most common aging-related diseases in western countries, while its prevalence in Asian countries with diets rich in antioxidants is much less frequent. Therefore many studies have been focused in the use of some antioxidants as chemopreventive agents. We have shown that the antioxidant pineal indole melatonin halts cell proliferation and induces neuroendocrine like differentiation in human epithelial prostate cancer cells The goal of the present study was to compare the actions of melatonin as a potential neuroendocrine--like differentiating agent with androgen withdrawal-induced NE differentiation, regarding the main role of androgen receptor.

Methods: 

We used confocal microscopy and protein levels of neuroendocrine markers to compare the phenotype of androgen-deprived or melatonin treated androgen dependent prostate cancer cells. Additionally we employed a whole genome microarray to compare the gene expression profiling between melatonin treated and androgen-deprived prostate cancer cells, in order to study potential gene expression pathways involved in androgen regulation. Finally, androgen receptor nuclear translocation was localized and quantified by using confocal microscopy and western blotting.

Results: 

Both, melatonin and androgen deprivation induces neuroendocrine-like differentiation with similar morphological and biochemical patterns. Genome microarray assay shows that both melatonin and androgen deprivation shares a common gene expression profiling. Androgen metabolism-related genes are not altered in melatonin treated cells, although some androgen-regulated genes (i.e. kallikrein) are profoundly downregulated in both groups. More interestingly, melatonin is able to prevent androgen receptor activation, keeping it in the cytosol after testosterone stimulation.

Conclusion: 

Melatonin, also at pharmacological concentrations, shows anti-androgenic properties in prostate cancer cells by sequestering AR in the cytoplam, without changing any androgen-metabolism-related genes.