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-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.
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Beatriz
B
Gil-Araujo
Departamento de Biología Celular y Genética, Universidad de Alcalá, Madrid, Spain; IRYCIS, Instituto de Investigaciones Sanitarias Ramón y Cajal, Madrid, Spain.
María-Val
MV
Toledo Lobo
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
María
M
Gutiérrez-Salmerón
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain.
Julia
J
Gutiérrez-Pitalúa
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Alcalá, Madrid, Spain.
Santiago
S
Ropero
Servicio de Urología, Hospital Universitario de Getafe, Madrid, Spain.
Javier C
JC
Angulo
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Alcalá, Madrid, Spain.
Antonio
A
Chiloeches
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas Alberto Sols CSIC-UAM, Arturo Duperier 4, 28029 Madrid, Spain. Electronic address: mlasa@iib.uam.es.
Marina
M
Lasa
D017209:Apoptosis; D045744:Cell Line, Tumor; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
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