Epac inhibits migration and proliferation of human prostate carcinoma cells.
BACKGROUND
It was recently found that cAMP mediates protein kinase A-independent effects through Epac proteins. The aim of this study was to investigate the role of Epac in migration and proliferation of prostate carcinoma cells.


METHODS
The effect of Epac activation was determined by [(3)H]thymidine incorporation and scratch assays in PC-3 and DU 145 cells. Furthermore, cytoskeletal integrity was analysed by phalloidin staining. The participation of intracellular Epac effectors such as mitogen-activated protein (MAP) kinases, Rap1- and Rho-GTPases was determined by immunoblotting and pull-down assay.


RESULTS
The specific Epac activator 8-pCPT-2'-O-Me-cAMP (8-pCPT) interfered with cytoskeletal integrity, reduced DNA synthesis, and migration. Although 8-pCPT activated Rap1, it inhibited MAP kinase signalling and RhoA activation. These findings were translated into functional effects such as inhibition of mitogenesis, cytoskeletal integrity, and migration.


CONCLUSIONS
In human prostate carcinoma cells, Epac inhibits proliferative and migratory responses likely because of inhibition of MAP kinase and RhoA signalling pathways. Therefore, Epac might represent an attractive therapeutic target in the treatment of prostate cancer.
Grandoch
M
M
Department of Pharmacology, University of Essen Medical School, Essen, Germany. maria.grandoch@uk-essen.de
Rose
A
A
ter Braak
M
M
Jendrossek
V
V
Rübben
H
H
Fischer
J W
JW
Schmidt
M
M
Weber
A A
AA
D000199:Actins / Q000032:analysis; D015820:Cadherins / Q000032:analysis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology
C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; D000199:Actins; D015820:Cadherins; D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D000242:Cyclic AMP; D020742:rhoA GTP-Binding Protein