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

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• 作者：Beatriz Gil-Araujo ; Mar铆a-Val Toledo Lobo ; Mar铆a Guti茅rrez-Salmer贸n ; Julia Guti茅rrez-Pital煤a ; Santiago Ropero ; Javier C. Angulo ; Antonio Chiloeches ; Marina Lasa
• 关键词：Dual specificity phosphatase 1 ; NF-魏B ; Apoptosis ; p38 MAPK ; Prostate cancer
• 刊名：Molecular Oncology
• 出版年：February, 2014
• 年：2014
• 卷：8
• 期：1
• 页码：27-38
• 全文大小：2707 K

文摘

Dual specificity phosphatase 1 (DUSP1) and the transcription factor NF-魏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-魏B activity by blocking p65/NF-魏B nuclear translocation. Moreover, although DUSP1 impairs TNF-伪-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-魏B activity. Consistently, DUSP1 promotes apoptosis and decreases NF-魏B activity in cells in which p38 MAPK is induced by TNF-伪 treatment. These results demonstrate that p38 MAPK is specifically involved in DUSP1-mediated effects on both apoptosis and NF-魏B activity. Interestingly, we show an inverse correlation between DUSP1 expression and activation of both p65/NF-魏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-魏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-魏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-魏B. Furthermore, our findings suggest that the ratio between DUSP1 and p65/NF-魏B expression levels, rather than the individual expression of both molecules, is a better marker for diagnostic purposes in prostate cancer.