Mitogenic activation of human prostate‐derived fibromuscular stromal cells by bradykinin

Abstract

1 Biologically active kinin peptides are released from precursor kininogens by kallikreins. Kinins act on kinin receptors to mediate diverse biological functions including smooth muscle contraction, in¯ammation, pain and mitogenicity. All components of the kallikrein-kinin system exist in human male genital secretions suggesting that these molecules participate in physiological and pathophysiological genitourinary function. The objective of this study was to assess the consequences of kinin action on prostate cells. 2 Primary cultures of prostate secretory epithelial (PE) and prostate ®bromuscular stromal (PS) cells were established from human prostate tissue. Transcripts encoding both the human B1 and B2 bradykinin receptor subtypes were detected in human prostate transition-zone tissue and in cultured cells by RT ± PCR. In receptor binding assays, the B1 subtype predominated on PE cell membranes and the B2 subtype predominated on PS cell membranes. In PS cells, but not in PE cells, BK induced signi®cant inositol phosphate accumulation and [ 3 H]-thymidine uptake. These responses were mediated through the B2 receptor subtype. 3 The use of signal transduction inhibitors indicated that mitogenic activation by BK occurred through both protein kinase C (PKC) and protein tyrosine kinase dependent mechanisms. PMA (phorbol 12-myristate 13-acetate) produced maximal [ 3 H]-thymidine uptake by PS cells, resulted in cell elongation and caused the a-actin ®bres present in PS smooth muscle cells to became organized into parallel arrays along the length of the elongated cells. 4 In summary, the prostate contains a functional kallikrein-kinin system, which could be signi®cant in physiological and pathophysiological prostate function.

Antiproliferative Efficacy of Angiotensin II Receptor Blockers in Prostate Cancer

“…The fact that ERK phosphorylation was noted during treatment with carbachol in androgenindependent PC-3 and DU145 cells, but not in androgendependent LNCaP cells, suggests that GPCR-mediated proliferation may be involved in androgen-independent prostate cancer [165]. Prostate cells not only express GPCRs but also produce GPCR ligands, which seem to act on cell proliferation in an autocrine or paracrine fashion [164,166,167]. For example, prostatic epithelial cells synthesize Ang-II by themselves, and Ang-II may induce proliferation of epithelial and stromal cells, which is defined as an autocrine and paracrine loop of the intrinsic RAS in the prostate gland.…”

Intratesticular Bradykinin Involvement in Rat Testicular Pain Models

“…Such chronic inflammation is considered to enhance the activity of afferent C fibers, including pain, which is the symptom that distinguishes CP/CPPS from other voiding dysfunctions . Given that bradykinin has been detected in human prostate tissue as well as in the conditioned medium of human prostate‐derived stromal cells in culture, elevated bradykinin levels in the prostate due to chronic inflammation likely contribute to pain in patients with CP/CPPS. The pain behavior induced by intratesticular injection of 1 mmol/L bradykinin disappeared at 20 min and that by 1% acetic acid at 1 h, from which these models were considered acute urogenital pain models.…”

“…All components of the kallikrein‐kinin system exist in human male genital secretions, suggesting that these molecules participate in physiological and pathophysiological genitourinary function. Indeed, bradykinin has been detected in human prostate tissue as well as in the conditioned medium of human prostate‐derived stromal cells in culture . In addition, bradykinin involvement in the regulation of bladder function has been proven in studies demonstrating that both B1 and B2 receptor antagonists can reduce bladder overactivity in a rat model of cyclophosphamide‐induced cystitis and in a rat model of spinal cord injury .…”

Kinin Receptors and Their Antagonists as Novel Therapeutic Agents

“…Activation of B 1 receptors has been reported to promote the formation of collagen and mitosis [184,185]. This effect seems to be triggered by the activation of B 2 receptors [187]. BK also shows mitogenic activity on human prostatederived fibromuscular stromal cells.…”

“…However, recent studies have suggested that endogenous kinins protect various tissues including myocardium against noxious stimuli [19][20][21][22]. Proliferative effects of kinins may play a role in their protective effects [181][182][183][184][185][186][187]. Tissue injury also causes an increase in the expression of B 1 -receptors as well as kinin levels [225].…”