B1 but not B2 bradykinin receptor agonists promote DU145 prostate cancer cell proliferation and migration

Abstract

Background: The kallikrein-kinin system (KKS) is an endogenous pathway involved in angiogenesis and tumourigenesis, both vital for cancer growth and progression. Objectives: To investigate the effect of two bradykinin receptor (B1R and B2R) agonists on growth and motility of prostate tumour (DU145) and micro-vascular endothelial cells (dMVECs). Methods: Increasing concentrations of selective B1R and B2R agonists were added to cultured cells. Cell proliferation and migration were assessed using the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and modified Boyden Chamber assays, respectively. Where significant stimulation was found, the influence of an antagonist was also investigated. Results: Neither growth nor motility of endothelial cells was affected by either agonist. In DU145 cells, while the B2R agonist was without any significant effect, the B1R agonist stimulated proliferation and migration at concentrations of 10nM and 50nM respectively. Further, this effect was abrogated when cells were pre-incubated with a B1R antagonist. Conclusions: Unlike the physiologically-active B2R, the pathologically-inducible B1R may be implicated in prostate tumourigenic events. The involvement of the KKS in malignant prostate pathology supports on-going exploration of bradykinin receptor antagonists as target candidates in the development of alternate approaches to cancer therapy.

Use of deuterium labeling by high‐temperature solid‐state hydrogen‐exchange reaction for mass spectrometric analysis of bradykinin biotransformation

“…BK exhibits potent cardioprotective and hypotensive effects and with its metabolites is crucial for the treatment of type 2 diabetes mellitus and glioblastoma . The bradykinin receptors B1R and B2R are important targets for the development of alternative approaches to prostate cancer therapy . Thus, in this context, BK appears to be a good model molecule demonstrating applicability of uniformly deuterated peptides for quantitative liquid chromatography/mass spectrometry (LC/MS) analysis of peptides and their degradation metabolites.…”

Activation of the human keratinocyte B1 bradykinin receptor induces expression and secretion of metalloproteases 2 and 9 by transactivation of epidermal growth factor receptor

“…Apparently, stimulation of BDKRB1 produces opposite effects on cell migration depending on the cell type involved. Whereas BDKRB1 promotes cell migration in some cancer cells, and human neutrophils , it inhibits migration of vascular smooth muscle and dendritic cells . Our in vitro experiments indicate that LDBK produces weak keratinocyte migration and pretreatment of cells with 1 n m LDBK delays keratinocyte migration induced by EGF, suggesting that BDKRB1 may negatively modulate EGFR action during wound healing.…”

Human Tissue Kallikrein 1 Is Downregulated in Elderly Human Prostates and Possesses Potential In Vitro Antioxidative and Antifibrotic Effects in Rodent Prostates

“…Therefore, we believed that at least in our experiments, BK had a beneficial effect on the prostate by promoting the production of NO via vascular endothelium, and because of its rapid degradation, BK did not obviously cause the proliferation or contraction of rat prostate stromal cells in vivo . Additionally, Naidu et al indicated that BK could mediate metastasis and invasion of the prostate cancer cells, even associated with angiogenesis [ 42 ]. However, in benign cases, the benefits and disadvantages of KKS for the prostate are worthy of discussion.…”