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.
Mol Oncol
; 8(1): 27-38, 2014 Feb.
Article
in En
| MEDLINE
| ID: mdl-24080497
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.
Key words
Apoptosis; BPH; DUSP1; Dual specificity phosphatase 1; FITC; MAPK; NF-κB; PARP; PC; PI; PIN; Prostate cancer; TMRM; TNF-α; benign prostatic hyperplasia; fluorescein isothiocyanate; mitogen-activated protein kinase; nuclear factor κb; p38 MAPK; poly (ADP-ribose) polymerase; propidium iodide; prostatic adenocarcinoma; prostatic intraepithelial neoplasia; tetramethylrhodamine methyl ester; tumor necrosis factor alpha
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Prostate
/
Prostatic Neoplasms
/
NF-kappa B
/
Apoptosis
/
P38 Mitogen-Activated Protein Kinases
/
Dual Specificity Phosphatase 1
Limits:
Humans
/
Male
Language:
En
Journal:
Mol Oncol
Journal subject:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Year:
2014
Document type:
Article
Affiliation country:
Spain
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA