Bradykinin‐induced cell migration and COX‐2 production mediated by the bradykinin B1 receptor in glioma cells

Abstract

Bradykinin is produced and acts at the site of injury and inflammation. Recent reports have also shown that bradykinin selectively modulates blood-tumor barrier permeability. However, the molecular mechanisms and pathologic roles underlying bradykinin-induced glioma migration remain unclear. Glioma is the most common primary adult brain tumor, with a poor prognosis because of the ease with which tumor cells spread to other regions of the brain. In this study, we found that bradykinin increases the cell migration and expression of cyclo-oxygenase-2 (COX-2) in glioma cells. Bradykinin-mediated migration was attenuated by the selective COX-2 inhibitor NS-398. Moreover, increased motility of glioma cells and expression of COX-2 were mimicked by a bradykinin B1 receptor (B1R) agonist and markedly inhibited by a B1R antagonist. Bradykinin-mediated migration was attenuated by phosphoinositide 3-kinase (PI-3 kinase)/AKT inhibitors LY 294002 and wortmannin. Bradykinin stimulation also increased the phosphorylation of the p85 subunit of PI-3 kinase and serine 473 of AKT. Treatment of bradykinin with AP-1 inhibitors Tanshinone IIA and curcumin also reduced COX-2 expression and glioma cell migration. Moreover, treatment of bradykinin also induced phosphorylation of c-Jun in glioma cells. AP-1 promoter analysis in the luciferase reporter construct showed that bradykinin increased AP-1 transcription activity and was inhibited by LY 294002 and wortmannin. One mechanism underlying bradykinin-directed migration is transcriptional up-regulation of COX-2 and activation of the B1R receptor, PI-3 kinase, AKT, c-Jun, and AP-1 pathways.

Glioblastoma‐mesenchymal stem cell communication modulates expression patterns of kinin receptors: Possible involvement of bradykinin in information flow

“…1-3). This is in accordance with recent results published by Lu et al (27), demonstrating that two human GBM cell lines U-138-MG and U-251-MG express functional B1R and B2R. They showed that proliferative effects were induced by incubation with DBK and BK.…”

“…In vivo studies on kinin B1 (B1R) and B2 receptors (B2R) revealed that B2R was increasingly expressed with augmenting malignancy of glioma (16) and GBM cells (26). Reportedly, B1R was not relevant for GBM cell invasion (15); however, B1R expression upregulation in GBM cells was confirmed by Lu et al (27). In GBM tissue, B1R expression may be induced by high levels of inflammatory cytokines produced by tumor infiltrating immune cells (28).…”

GPCRs and cancer

“…Recently, Ang-II exhibited in vitro and in vivo the potential to enhance the expression of AR in prostate cancer cells through angiotensin II type-1 receptor (AT1R) [106] . In addition, Ang-II and BK receptors have been implicated in the development, growth, angiogenesis and metastasis in a wide number of tumors [101,102,[107][108][109][110][111] . For instance, Ang-II and BK stimulated DNA synthesis in pancreatic cancer cells [112] .…”

“…For instance, Ang-II and BK stimulated DNA synthesis in pancreatic cancer cells [112] . In the context of this malignancy, a cross-talk between insulin/ insulin like growth factor-I (IGF-1) receptors and Ang-II and BK-activated GPCRs has been reported [111][112][113][114] . In particular, insulin induced the potentiation of Ang-II and BK-dependent signaling through the PI3K/Akt/mTOR transduction pathway [113] .…”

O papel do receptor B1 da bradicinina em modelos experimentais de lesão pulmonar aguda direta e indireta.

“…Outros estudos utilizando modelo de isquemia e reperfusão cerebral em ratos ou camundongos nocautes para os receptores de bradicinina mostraram que o B1R contribui para a lesão cerebral enquanto o B2R é benéfico [85,86]. Este efeito deletério de B1R também foi demonstrado em um modelo de colite e tumor cerebral [87,88].…”