Activation of protein kinase B/Akt by alpha1-adrenoceptors in the human prostate

Aims: Besides their role in contraction, alpha 1-adrenoceptors may be involved in prostate hyperplasia. This would require receptor signaling by growth-promoting pathways. Akt (syn. Protein kinase B) is an important regulator of growth and differentiation. Objective: To investigate whether alpha 1-adrenoceptors in the human prostate activate Akt. Main methods: Prostate tissue was obtained from patients undergoing radical prostatectomy. Akt expression was investigated by RT-PCR. Western blot, and immunohistochemistry. Akt activation by noradrenaline (30 mu M) and phenylephrine (10 mu M) was assessed by Western blot analyses with a phospho-specific antibody. The effects of the Akt inhibitors FPA-124 and 10-DEBC on phenylephrine-, noradrenaline- and electric field stimulation- (EFS-) induced contraction were studied in myographic measurements. Key findings: mRNA of all three Akt isoforms (Akt1, Akt2, Akt3) was detected by RT-PCR in all prostate samples (n = 6 patients). Protein expression was confirmed by Western blot analysis (n = 8 patients). Immunohistochemical staining for Akt revealed strong immunoreactivity in prostate smooth muscle cells (n = 5 patients). Stimulation of prostate tissues with noradrenaline (30 mu M, n = 8 patients) or phenylephrine (10 mu M, n=7 patients) caused significant Akt phosphorylation at serine-473, indicating activation of Akt. FPA124 and 10-DEBC were without effects on noradrenaline-, phenylephrine-, or EFS-induced contraction of prostate strips. Significance: Prostate alpha 1-adrenoceptors activate Akt. Consequently, Akt is a target of alpha 1-blocker therapy, which has been unknown to date. Our findings point to functions of prostate alpha 1-adrenoceptors besides contraction. (C) 2012 Elsevier Inc. All rights reserved.