Bradykinin enhances cell migration in human prostate cancer cells through B2 receptor/PKCδ/c-Src dependent signaling pathway.
BACKGROUND
Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to the bone. Bradykinin (BK) is an inflammatory mediator, and shows elevated levels in regions of severe injury and inflammatory diseases. The aim of this study was to investigate whether Bradykinin is associated with migration of prostate cancer cells.


METHODS
Cancer cells migration activity was examined using the Transwell assay. The c-Src and PKCδ phosphorylation was examined by using Western blot method. The qPCR was used to examine the mRNA expression of metalloproteinase. A transient transfection protocol was used to examine NF-κB activity.


RESULTS
We found that bradykinin increased the chemomigration and the expression of MMP-9 of human prostate cancer cells. Bradykinin-mediated chemomigration and metalloproteinase expression was attenuated by PKCδ inhibitor (rottlerin), PKCδ siRNA, c-Src inhibitor (PP2) and c-Src mutant. Activations of PKCδ, c-Src and NF-κB pathways after bradykinin treatment was demonstrated, and bradykinin-induced expression of metalloproteinase and chemomigration activity was inhibited by the specific inhibitor and mutant of PKCδ, c-Src, and NF-κB cascades.


CONCLUSIONS
This study showed for the first time that the bradykinin mediates migration of human prostate cancer cells. One of the mechanisms underlying bradykinin directed migration was transcriptional up-regulation of MMP-9 and activation of B2 receptor, PKCδ, c-Src, and NF-κB pathways.
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Hsin-Shan
HS
Yu
Tien-Huang
TH
Lin
Chih-Hsin
CH
Tang
D000098:Acetophenones / Q000494:pharmacology; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D001578:Benzopyrans / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism*
D000098:Acetophenones; D001578:Benzopyrans; D016328:NF-kappa B; D034741:RNA, Small Interfering; D043782:Receptor, Bradykinin B2; C085746:rottlerin; D019061:src-Family Kinases; D051745:Protein Kinase C-delta; D020780:Matrix Metalloproteinase 9; D001920:Bradykinin