In benign prostatic hyperplasia, smooth muscle contraction in the prostate drives urethral obstruction, which may result in lower urinary tract symptoms. Consequently, inhibition of contraction is an important strategy for medical therapy, but available options still show insufficient efficacy. Development of future options with higher efficacy requires adequate understanding of contractile mechanisms and identification of novel targets in the prostate. Recently, a possible role of polo-like kinase 1 (PLK1) has been suggested for smooth muscle contraction outside the lower urinary tract, and small molecule PLK1 inhibitors have become available. Here, we examined effects of PLK1 inhibitors on contraction of human prostate tissue.
Prostate tissues were obtained from radical prostatectomy (n=122 patients). Smooth muscle contractions were studied in an organ bath, where they were induced by α1-adrenoceptor agonists or electric field stimulation (EFS) after addition of solvent (control) or PLK inhibitor (SBE13, cyclapolin 9, TAK960, Ro-3280). RT-PCR, Western blot and immunofluorescence were performed for detection of PLK isoforms.
Noradrenaline and the α1-agonists phenylephrine and methoxamine (each 0.1-100 µM) induced concentration-dependent contractions of human prostate strips, which were significantly inhibited by SBE13 (1 µM) and cyclapolin 9 (3 µM). This inhibition was significant for different agonist concentrations, and between groups for nearly all agonist/inhibitor combinations (p<0.01, p<0.002, p).
PLK inhibitors inhibit α1-adrenergic and neurogenic smooth muscle contractions in the prostate. The PLK pathway may be important and unique for promoting α1-adrenergic contraction, as non-adrenergic contractions are resistant to PLK inhibition. A PLK-dependent signalling pathway may confer divergent regulation of adrenergic and non-adrenergic contraction in the human prostate.