Neuropeptide Y and its Y2 receptor: potential targets in neuroblastoma therapy

Abstract

Neuroblastomas are pediatric tumors which develop from sympathetic precursors and express neuronal proteins, such as neuropeptide Y (NPY). NPY is a sympathetic neurotransmitter acting via multiple receptors (Y1-Y5R). Both NPY and Y2Rs are commonly expressed in neuroblastoma cell lines and tissues. The peptide secreted from neuroblastomas stimulates tumor cell proliferation and angiogenesis. Since both processes are Y2R-mediated, the goal of this study was to assess Y2R as a potential therapeutic target for neuroblastoma. In vitro, Y2R antagonist (BIIE0246) prevented activation of p44/42 MAPK induced by endogenous NPY, which resulted in decreased proliferation and induction of Bim-mediated apoptosis. Similar growth-inhibitory effects were achieved with NPY siRNA and Y2R siRNA. In vivo, Y2R antagonist significantly inhibited growth of SK-N-BE(2) and SK-N-AS xenografts, which was associated with decreased activation of p44/42 MAPK, as well as reduced proliferation (Ki67) and increased apoptosis (TUNEL). The Y2R antagonist also exerted an anti-angiogenic effect. In vitro, it reduced the proliferation of endothelial cells induced by neuroblastoma-conditioned media. Consequently, the Y2R antagonist-treated xenografts had decreased vascularization and a high degree of focal fibrosis. In human neuroblastoma tissues, the expression of Y2R was observed in both tumor and endothelial cells, while NPY was predominantly expressed in neuroblastoma cells. In summary, Y2R is a promising new target for neuroblastoma therapy affecting both cancer cells and tumor vasculature.

Sympathetic Neurotransmitters in Neuroblastoma – Between Physiology and Pathology

“…5) (Kitlinska et al, 2005). More importantly, blocking the NPY/Y2R mitogenic signaling reduces basal levels of p44/42 MAPK activity in neuroblastoma cells and significantly inhibits their proliferation (Lu et al, 2010). This effect is associated with an increase in neuroblastoma cell apoptosis mediated by the Bim pathway, known to be activated upon growth factor withdrawal (Lu et al, 2010).…”

Neuroblastoma therapy: what is in the pipeline?

“…NPY induces NB tumour growth and angiogenesis (Kitlinska et al 2005). NY2R is the most common NPY receptor expressed in NB cells and blocking the binding of NPY to NY2R has been proposed as an approach to inhibit NB growth (Lu et al 2010). It has been shown that blocking NY2R results in a decrease in NB proliferation rate, it induces apoptosis and in vivo studies show an impairment of the tumour vascularisation as well (Lu et al 2010).…”

“…We recently proposed to target doublecortin-like kinase (DCLK1) to inhibit NB proliferation and induce apoptosis (Verissimo et al 2010). In addition, neuropeptide Y (NPY) and its Y2 receptor (NY2R) were selected as examples of antiangiogenesis targets (Lu et al 2010). The high expression levels of the sympathetic neurotransmitter NPY correlates with MYCN amplification and with poor clinic outcome (Dötsch et al 1998).…”

“…The pro-angiogenic phenotype is NPY has also been shown to stimulate angiogenesis and NB proliferation (Cohen et al 1990). NPY is a sympathetic neurotransmitter, which acts through G-protein-coupled receptors (Y1-Y5; Lu et al 2010). NPY is a growth factor for various cells including endothelial cells and neuronal precursors (Movafagh et al 2006, Lu et al 2010.…”

“…NY2R is the most common NPY receptor expressed in NB cells and blocking the binding of NPY to NY2R has been proposed as an approach to inhibit NB growth (Lu et al 2010). It has been shown that blocking NY2R results in a decrease in NB proliferation rate, it induces apoptosis and in vivo studies show an impairment of the tumour vascularisation as well (Lu et al 2010). Therefore, there are strong indications that targeting angiogenesis is a promising approach, being NPY, NY2R and/or other proteins involved in this tumorigenic process (Table 2) targets to consider for NB therapy.…”