Abstract
Recently, a new experimental stromal hyperplasia animal model corresponding to clinical benign prostatic hyperplasia (BPH) was established. The main objective of this study was to elucidate the roles of the intermediate-conductance Ca2+-activated K+ channel (KCa3.1) in the implanted urogenital sinus (UGS) of stromal hyperplasia BPH model rats. Using DNA microarray, real-time polymerase chain reaction, Western blot, and/or immunohistochemical analyses, we identified the expression of KCa3.1 and its transcriptional regulators in implanted UGS of BPH model rats and prostate needle-biopsy samples and surgical prostate specimens of BPH patients. We also examined the in vivo effects of a KCa3.1 blocker, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), on the proliferation index of implanted UGS by measurement of UGS weights and proliferating cell nuclear antigen immunostaining. KCa3.1 genes and proteins were highly expressed in implanted UGS rather than in the normal host prostate. In the implanted UGS, the gene expressions of two transcriptional regulators of KCa3.1, repressor element 1-silencing transcription factor and c-Jun, were significantly down- and up-regulated, and the regulations were correlated negatively or positively with KCa3.1 expression, respectively. Positive signals of KCa3.1 proteins were detected exclusively in stromal cells, whereas they were scarcely immunolocalized to basal cells of the epithelium in implanted UGS. In vivo treatment with TRAM-34 significantly suppressed the increase in implanted UGS weights compared with the decrease in stromal cell components. Moreover, significant levels of KCa3.1 expression were observed in human BPH samples. KCa3.1 blockers may be a novel treatment option for patients suffering from BPH.
Footnotes
This work was supported by Grants-in Aid for Scientific Research from the Japan Society for the Promotion of Science [Grants 20390027, 21590098] (to Y.I. and S.O., respectively); Takeda Science Foundation (to S.O.); and Salt Science Research Foundation [Grant 10C6] (to S.O.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.182782.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- BPH
- benign prostate hyperplasia
- KCa3.1
- intermediate-conductance Ca2+-activated K+ channel
- VSMC
- vascular smooth muscle cell
- REST
- repressor element 1-silencing transcription factor
- UGS
- urogenital sinus
- AP-1
- activator protein-1
- PCR
- polymerase chain reaction
- bp
- base pair
- KCa
- Ca2+-activated K+ channel
- IKCa
- intermediate-conductance KCa channel
- PCNA
- proliferating cell nuclear antigen
- TRAM-34
- 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole
- KCa1.1
- large-conductance Ca2+-activated K+ channel.
- Received April 7, 2011.
- Accepted May 19, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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