title: Inhibition of smooth muscle force generation by focal adhesion kinase inhibitors in the hyperplastic human prostate.
abstract: Smooth muscle contraction may be critical for lower urinary tract symptoms (LUTS) in patients with benign prostate hyperplasia and requires stable anchorage of the cytoskeleton to the cell membrane. These connections are regulated by focal adhesion kinase (FAK). Here, we addressed the involvement of FAK in the regulation of smooth muscle contraction in hyperplastic human prostate tissues. Prostate tissues were obtained from radical prostatectomy. Expression of FAK and focal adhesion proteins was assessed by Western blot analysis and immunohistochemical stainings. Effects of the FAK inhibitors PF-573228 and Y-11 on contraction of prostate strips were examined in the organ bath. Expression of FAK and focal adhesion proteins (integrin-5α, paxilin, and c-Src) was detected by Western blot analysis in prostate samples. By double immunofluorescence staining with calponin and pan-cytokeratin, expression of FAK was observed in stromal and epithelial cells. Immunoreactivity for FAK colocalized with integrin-5α, paxilin, talin, and c-Src. Stimulation of prostate tissues with the α1-adrenergic agonist phenylephrine increased the phosphorylation state of FAK at Tyr³⁹⁷ and Tyr⁹²⁵ with different kinetics, which was blocked by the α1-adrenoceptor antagonist tamsulosin. Norepinephrine and phenylephrine induced concentration-dependent contractions of prostate strips. Both FAK inhibitors PF-573228 and Y-11 significantly inhibited norepinephrine- and phenylephrine-induced contractions. Finally, PF-573228 and Y-11 inhibited contractions induced by electric field stimulation, which was significant at the highest frequency. In conclusion, α1-adrenergic smooth muscle contraction or its regulation involves FAK in the human prostate. Consequently, FAK may be involved in the pathophysiology of LUTS and in current or future LUTS therapies.
authors: Department of Urology, Ludwig-Maximilians University, Munich, Germany; Krankenhaus der Barmherzigen Schwestern Linz, Linz, Austria; and.
authors: Thomas
authors: T
authors: Kunit
authors: Department of Urology, Ludwig-Maximilians University, Munich, Germany; christian.gratzke@med.uni-muenchen.de.
authors: Christian
authors: C
authors: Gratzke
authors: Department of Urology, Ludwig-Maximilians University, Munich, Germany;
authors: Andrea
authors: A
authors: Schreiber
authors: Department of Urology, Ludwig-Maximilians University, Munich, Germany;
authors: Frank
authors: F
authors: Strittmatter
authors: Department of Urology, Ludwig-Maximilians University, Munich, Germany;
authors: Raphaela
authors: R
authors: Waidelich
authors: Department of Urology, Ludwig-Maximilians University, Munich, Germany;
authors: Beata
authors: B
authors: Rutz
authors: Krankenhaus der Barmherzigen Schwestern Linz, Linz, Austria; and.
authors: Wolfgang
authors: W
authors: Loidl
authors: Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
authors: Karl-Erik
authors: KE
authors: Andersson
authors: Department of Urology, Ludwig-Maximilians University, Munich, Germany;
authors: Christian G
authors: CG
authors: Stief
authors: Department of Urology, Ludwig-Maximilians University, Munich, Germany;
authors: Martin
authors: M
authors: Hennenberg
mesh_terms: D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006572:Heterocyclic Compounds, Bridged-Ring; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism; D010656:Phenylephrine; D010766:Phosphorylation; D011467:Prostate / Q000201:enzymology*; D015363:Quinolones; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013450:Sulfones
chemical_list: C574188:1-(2-hydroxyethyl)-3,5,7-triaza-1-azoniatricyclo(3.3.1.1(3,7))decane bromide; C521108:6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one; D006572:Heterocyclic Compounds, Bridged-Ring; D018994:Myosin Light Chains; D015363:Quinolones; D018340:Receptors, Adrenergic, alpha-1; D013450:Sulfones; D010656:Phenylephrine; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: benign prostate hyperplasia; focal adhesion kinase; lower urinary tract symptoms; smooth muscle contraction; α1-adrenoceptor