Vasoactive intestinal peptide (VIP) stimulates rat prostatic epithelial cell proliferation

Abstract

BACKGROUND. Androgens play a major role in supporting normal growth and functional maintenance in the prostate. However, this gland contains an array of neuroendocrine peptides that can play a regulatory role in its physiopathology. Among these peptides, one of the best studied is vasoactive intestinal peptide (VIP), which is abundant in autonomic nerves surrounding both human and rat prostatic acini. This neuropeptide may act through interaction with two types of high-af®nity receptors, named VPAC 1 and VPAC 2 receptors. Another regulatory peptide, the pituitary adenylate cyclase-activating peptide (PACAP), interacts with these receptors with the same af®nity as VIP, but binds with higher af®nity to PAC 1 receptors. Human prostate tumors and rat prostate show a major presence of VPAC 1 receptors, whereas various ®ndings suggest a role for VIP in prostatic development. Here we studied the effects of VIP on the proliferation of rat prostatic epithelial cells in culture. METHODS. We studied the [ 3 H]-thymidine uptake by rat prostatic epithelial cells in culture, characterized previously by using biomarkers such as cytokeratin and vimentin. In these cells we tested the effect of VIP and PACAP-27 on two different signaling pathways, the cyclic AMP (cAMP) and the inositol phosphate (IPs). RESULTS. The rat prostatic cells in culture were cytokeratin (5,6,8) and vimentin positive, indicating that the culture was predominantly epithelial. The proliferation curves showed that the cells followed different states of growth: a quiescent, an exponential proliferative, and a steady state. Cyclic AMP production, but not inositol phosphate production, was increased in the presence of VIP and PACAP-27, which suggests the expression of VPAC 1 and/or VPAC 2 receptors primarily. VIP signi®cantly increased prostatic cell proliferation in a bimodal manner, as shown for dibutyryl cyclic AMP (dbcAMP), which suggests that the effect of VIP upon prostatic proliferation is cAMP-dependent. CONCLUSIONS. Here, we demonstrate that VIP increased [ 3 H]thymidine uptake by rat prostatic epithelial cells in culture, conceivably by the activation of the adenylate cyclase.

Vasoactive intestinal peptide induces neuroendocrine differentiation in the LNCaP prostate cancer cell line through PKA, ERK, and PI3K

“…Vasoactive intestinal peptide (VIP) is a neuropeptide involved in the proliferation and/or differentiation of various normal and cancer cell lines [5,6]. Regarding the prostate, VIP and another structurally-related neuropeptide that share receptors with it, pituitaryadenylate cyclase activating polypeptide (PACAP), stimulate rat prostatic epithelial cell proliferation, induce NE differentiation in LNCaP cells (an androgen-dependent prostate cell line), and protect from apoptosis in PC-3 cells (an androgen-independent prostate cell line) [7][8][9][10]. These two neuropeptides exert their biological effects through specific receptors that belong to family 2 of GPCRs: VPAC 1 and VPAC 2 which recognize VIP and PACAP with the same affinity, and PAC 1 that recognizes PACAP with higher affinity than VIP [11].…”

“…Moreover, the expression of VIP receptors in rat prostate increases during puberty, a period with high rates of cell proliferation and differentiation [13,14]. VIP receptors are mainly coupled to adenylate cyclase as a signal transduction pathway in normal and cancer prostate cells [7][8][9][10]12,15]. In this context, there is an increasing interest on the role of cAMP in prostate cancer, since an increase of cAMP levels is related to the acquisition of NE phenotype by prostate cancer cells [16,17].…”

Evolution of Neuroendocrine Cell Population and Peptidergic Innervation, Assessed by Discriminant Analysis, During Postnatal Development of the Rat Prostate

“…At the present time, the peptidergic innervation of the prostate seems to play a role of special relevance in prostatic physiology (Dixon et al, 2000;Ventura et al, 2002). These neuropeptides, behaving as regulators of prostatic secretion, may be involved in modulation of the action of androgens (Gkonos et al, 1995;Juarranz et al, 2001;Ventura et al, 2002). Some studies associate VIP with the proliferation of prostatic acini in rats (Juarranz et al, 2001).…”

“…These neuropeptides, behaving as regulators of prostatic secretion, may be involved in modulation of the action of androgens (Gkonos et al, 1995;Juarranz et al, 2001;Ventura et al, 2002). Some studies associate VIP with the proliferation of prostatic acini in rats (Juarranz et al, 2001). It is also important to note the post-pubertal decrease of NPY immunoreactive periglandular fibres (Rodriguez et al, 2005).…”

“…For example, VIP could induce cell proliferation of the acini in rat prostate (Juarranz et al, 2001).…”