Abstract
The mammalian lignan, enterolactone, has been shown to reduce the proliferation of the earlier stages of prostate cancer at physiological concentrations in vitro. However, efficacy in the later stages of the disease occurs at concentrations difficult to achieve through dietary modification. We have therefore investigated what concentration(s) of enterolactone can restrict proliferation in multiple stages of prostate cancer using an in vitro model system of prostate disease. We determined that enterolactone at 20 μM significantly restricted the proliferation of mid and late stage models of prostate disease. These effects were strongly associated with changes in the expression of the DNA licencing genes (GMNN, CDT1, MCM2 and 7), in reduced expression of the miR-106b cluster (miR-106b, miR-93, and miR-25), and in increased expression of the PTEN tumour suppressor gene. We have shown anti-proliferative effects of enterolactone in earlier stages of prostate disease than previously reported and that these effects are mediated, in part, by microRNA-mediated regulation.
Highlights
Prostate cancer is the second most common cancer in men worldwide with seventy percent of annual diagnoses occurring in Westernised societies [1]
Enterolactone (ENL) is a weakly-oestrogenic (100 to 1000-fold less compared to natural oestradiol) mammalian metabolite that is produced by the metabolism of plant lignans by intestinal bacteria, but may be present in low amounts in dairy foods and meat as a consequence of ruminant intestinal metabolism, [12,13,14,15,16]
We have shown that the anti-proliferative effects of ENL are strongly associated with: (1) improved negative regulation of abnormal DNA licencing; and (2) inhibition of miR-106b cluster expression leading to increased expression of the tumour suppressive gene phosphatase and tensin homolog (PTEN)
Summary
Prostate cancer is the second most common cancer in men worldwide with seventy percent of annual diagnoses occurring in Westernised societies [1]. The LNCaP cell line is a model of the switch between androgen sensitivity and insensitivity during prostate disease that occurs in the later stages of carcinogenesis [37] This in vitro model system was used to assess how the metabolic activity, growth rate, cell cycle progression changes with ENL exposure over 24 and 48 h. Based on these data we explored potential mechanisms for the anti-proliferative activity by measuring the expression of the GMMN, CDT1, MCM2 and MCM7, miR-106b cluster, and PTEN genes
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