Abstract
The kallikrein-kinin system (KKS) is an endogenous pathway involved in angiogenesis and tumourigenesis, both vital for cancer growth and progression. 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). 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. 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. 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.
Highlights
The kallikrein-kinin system (KKS) consists of two serine proteases, plasma and tissue kallikrein (TK), that release bio-active kinin peptides by enzymatic cleavage of hepatically-derived kininogens 1
The KKS has been implicated in angiogenesis, the growth of new blood vessels from the pre-existing vasculature . 9,10 Several studies have demonstrated a role for TK in neo-vascularisation following hind-limb ischemia in murine models . 11-13 The KKS may be involved in tumour-associated angiogenesis, which is a pre-requisite for tumour growth and metastasis . 14-16 The Ishihara group showed that a selective B2R, but not B1R, antagonist suppressed tumour-angiogenesis in mice implanted with sarcoma 180 cells 15
This study further explores the role of the KKS in prostate cancer and angiogenesis by investigating the effect of kinin receptor agonists and antagonists on prostate tumour (DU145) and micro-vascular endothelial cell lines in vitro
Summary
The kallikrein-kinin system (KKS) consists of two serine proteases, plasma and tissue kallikrein (TK), that release bio-active kinin peptides by enzymatic cleavage of hepatically-derived kininogens 1. The expression profiles of TK and BK are altered in numerous human cancers, and several studies have implicated the KKS in growth and metastasis of prostate tumours: BK and BR agonists have been shown to stimulate proliferation, migration and invasion of PC3 prostate cancer cells in vitro , 3,6,7 while some have reported that an interaction with both BR sub-types may be vital for the proliferation of prostate cancer cells 6. 14-16 The Ishihara group showed that a selective B2R, but not B1R, antagonist suppressed tumour-angiogenesis in mice implanted with sarcoma 180 cells 15. 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). 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 This effect was abrogated when cells were pre-incubated with a B1R antagonist.
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