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. Issue 1 (14th September 2013)

• Record Type: Journal Article
• Authors: Gil-Araujo, Beatriz; Toledo Lobo, María-Val; Gutiérrez-Salmerón, María; Gutiérrez-Pitalúa, Julia; Ropero, Santiago; Angulo, Javier C.; Chiloeches, Antonio; Lasa, Marina
• Is Part Of: Molecular oncology. Volume 8:Issue 1(2014:Jan.)
• Page Start: 27
• Page End: 38
• Publication Date: 2013-09-14
• Subjects: Dual specificity phosphatase 1 -- NF-κB -- Apoptosis -- p38 MAPK -- Prostate cancer; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1016/j.molonc.2013.08.012
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Dual specificity phosphatase 1 (DUSP1) and the transcription factor NF‐κB 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‐κB activity by blocking p65/NF‐κB nuclear translocation. Moreover, although DUSP1 impairs TNF‐α‐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‐κB activity. Consistently, DUSP1 promotes apoptosis and decreases NF‐κB activity in cells in which p38 MAPK is induced by TNF‐α treatment. These results demonstrate that p38 MAPK is specifically involved in DUSP1‐mediated effects on both apoptosis and NF‐κB activity. Interestingly, we show an inverse correlation between DUSP1 expression and activation of both p65/NF‐κB 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‐κB 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‐κB 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‐κB. Furthermore, our findings suggest that the ratio between DUSP1 and p65/NF‐κB expression levels, rather than the individual expression of both molecules, is a better marker for diagnostic purposes in prostate cancer. Highlights: DUSP1 promotes apoptosis in prostate cancer cells through the inhibition of p38 MAPK DUSP1 impairs NF‐κB activity through a mechanism involving p38 MAPK inhibition. DUSP1 expression inversely correlates with NF‐κB in human prostate tissue specimens. The ratio DUSP1/NF‐κB can be useful for diagnostic purposes in prostate cancer.