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Vasoactive Intestinal Peptide Transactivates the Androgen Receptor through a Protein Kinase A-Dependent Extracellular Signal-Regulated Kinase Pathway in Prostate Cancer LNCaP Cells

Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska (Y.X., D.W.W., Y.T.); and Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska (M.F.L.)

Acquisition of androgen independence by prostate cancer is the key problem of prostate cancer progression. Vasoactive intestinal peptide (VIP), a neuropeptide, may act as a survival factor for prostate cancer cells under androgen deprivation. However, the molecular mechanisms by which VIP promotes the androgen-independent growth of androgen-sensitive prostate cancer cells have not been addressed. We therefore investigated the biological effect and signal pathway of VIP in LNCaP cells, a prostate cancer cell line that requires androgens for growth. We showed that low nanomolar concentrations of VIP, acting through G_s-protein-coupled VIP receptors, can induce LNCaP cell growth in the absence of androgen. Blockade of androgen-receptor (AR) in these cells by AR antagonist bicalutamide or by anti-AR small interfering RNA, inhibited the proliferative effect of VIP. In addition, VIP stimulated androgen-independent activation of AR with an EC₅₀ of 3.0 ± 0.8 nM. We then investigated VIP-stimulated signaling events that may interact with the AR pathway in prostate cancer cells. VIP regulation of AR activation, mediated by VIP receptors, was protein kinase A (PKA)-dependent, and extracellular signal-regulated kinase 1/2 (ERK1/2) activation contributes to VIP-mediated AR activation. Furthermore, PKA-dependent Rap1 activation is required for both ERK1/2 activation and androgen-independent AR activation in LNCaP cells upon VIP stimulation. Finally, we showed that VIP-induced AR activation was also present in prostate cancer CWR22Rv1 and PC3 cells transfected with the wild-type AR. Altogether, we demonstrate that VIP acting through its G_s-protein-coupled receptors can cause androgen-independent transactivation of AR through a PKA/Rap1/ERK1/2 pathway, thus promoting androgen-independent proliferation of androgen-sensitive prostate cancer cells.

Address correspondence to: Dr. Yaping Tu, Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178. E-mail: yapingtu{at}creighton.edu

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