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

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.

Capsaicin reduces genotoxicity, colonic cell proliferation and preneoplastic lesions induced by 1,2-dimethylhydrazine in rats

“…Conversely, capsaicin also induced the expression of NF-κB inhbitors, such as the genes Mapk3 Mapk14, and Smad4. Mapk14, also known as p38α, is a serine/threonine stress-activated protein kinase that is activated in response to a variety of extracellular stimuli, including genotoxic stress induced by chemicals (Igea and Nebreda 2015), promoting apoptosis and NF-κB regulation (Gil-Araujo et al 2014;Igea and Nebreda 2015;Olson et al 2007). In the colon, Smad4 downregulation leads to uncontrolled cell proliferation (Dienstmann et al 2017;Handra-Luca et al 2011).…”

The Stress Kinase p38α as a Target for Cancer Therapy

“…In the same line, the p38a pathway has been proposed to negatively regulate stemness of glioma-initiating cells, by inducing loss of self-renewal and promoting differentiation (15). Moreover, p38a is required for the survival of pancreas cancer cell lines and highgrade human pancreas tumors show enhanced levels of phosphorylated p38 MAPK, which correlate with reduced expression of the phosphatase DUSP1 (16).…”

Gemcitabine resistance in breast cancer cells regulated by PI3K/AKT-mediated cellular proliferation exerts negative feedback via the MEK/MAPK and mTOR pathways

“…Activation of Raf–mitogen-activated protein kinase kinase (MEK)–extracellular signal-regulated kinase (ERK) is critical for both normal and cancer cellular development 20. Antiproliferative and proapoptotic effects in breast cancer are mediated through p38 phosphorylation21 and it is also involved in apoptosis of prostate cancer 22. MAPK pathways also take part in many drug resistance patterns in cancer cells 23,24.…”