Dual specificity phosphatase 1 expression inversely correlates with NF-κB activity and expression in prostate cancer and promotes apoptosis through a p38 MAPK dependent mechanism

Dual specificity phosphatase 1 (DUSP1) and the transcription factor NF-kappa B are implicated in prostate cancer since their expression levels are altered along this disease, although there are no evidences up to date demonstrating a crosstalk between them. In this report, we show for the first time that DUSP1 over-expression in DU145 cells promotes apoptosis and decreases NF-kappa B activity by blocking p65/NF-kappa B nuclear translocation. Moreover, although DUSP1 impairs TNF-alpha-induced p38 MAPK and JNK activation, only the specific inhibition of p38 MAPK exerts the same effects than DUSP1 over-expression on both apoptosis and NF-kappa B activity. Consistently, DUSP1 promotes apoptosis and decreases NF-kappa B activity in cells in which p38 MAPK is induced by TNF-alpha treatment. These results demonstrate that p38 MAPK is specifically involved in DUSP1-mediated effects on both apoptosis and NF-kappa B activity. Interestingly, we show an inverse correlation between DUSP1 expression and activation of both p65/NF-kappa B and p38 MAPK in human prostate tissue specimens. Thus, most of apparently normal glands, benign prostatic hyperplasia and low-grade prostatic intraepithelial neoplasia samples show high DUSP1 expression and low levels of both nuclear p65/NF-kappa B and activated p38 MAPK. By contrast, DUSP1 expression levels are low or even absent in high-grade prostatic intraepithelial neoplasia and prostatic adenocarcinoma samples, whereas nuclear p65/NF-kappa B and activated p38 MAPK are highly expressed in the same samples. Overall, our results provide evidence for a role of DUSP1 in the apoptosis of prostate cancer cells, through a mechanism involving the inhibition of p38 MAPK and NF-kappa B. Furthermore, our findings suggest that the ratio between DUSP1 and p65/NF-kappa B expression levels, rather than the individual expression of both molecules, is a better marker for diagnostic purposes in prostate cancer. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.