VIP and PACAP analogs regulate therapeutic targets in high-risk neuroblastoma cells
Madryssa de Boisvilliers1, Florian Perrin1, Salima Hebache1
1Université de Poitiers, Équipe Récepteurs, Régulations et Cellules Tumorales (2RCT), Pôle Biologie Santé, Bât. B36/B37, UFR Sciences Fondamentales et Appliquées, 1 rue Georges Bonnet TSA, 51106 86073 Poitiers Cedex 9, France.
Abstract:
Neuroblastoma (NB) is a pediatric cancer. New therapies for high-risk NB aim to induce cell differentiation and to inhibit MYCN and ALK signaling in NB. The vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase-activating polypeptide (PACAP) are 2 related neuropeptides sharing common receptors. The level of VIP increases with NB differentiation. Here, the effects of VIP and PACAP analogs developed for therapeutic use were studied in MYCN-amplified NB SK-N-DZ and IMR-32 cells and in Kelly cells that in addition present the F1174L ALK mutation. As previously reported by our group in IMR-32 cells, VIP induced neuritogenesis in SK-N-DZ and Kelly cells and reduced MYCN expression in Kelly but not in SK-N-DZ cells. VIP decreased AKT activity in the ALK-mutated Kelly cells. These effects were PKA-dependent. IMR-32, SK-NDZ and Kelly cells expressed the genes encoding the 3 subtypes of VIP and PACAP receptors, VPAC1, VPAC2 and PAC1. In parallel to its effect on MYCN expression, VIP inhibited invasion in IMR-32 and Kelly cells. Among the 3 PACAP analogs tested, [Hyp(2)]PACAP-27 showed higher efficiency than VIP in Kelly cells. These results indicate that VIP and PACAP analogs act on molecular and cellular processes that could reduce aggressiveness of high-risk NB.
Insights
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) analogs show potential in treating high-risk neuroblastoma (NB). These neuropeptides may reduce cancer aggressiveness by inhibiting MYCN and ALK signaling and decreasing cell invasion.
Area of Science:
- Oncology
- Neuroscience
- Molecular Biology
Background:
- Neuroblastoma (NB) is a pediatric cancer with high-risk subtypes requiring novel therapies.
- Current treatments for high-risk NB focus on inducing cell differentiation and inhibiting MYCN and ALK signaling pathways.
- Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are neuropeptides linked to NB differentiation.
Purpose of the Study:
- To investigate the therapeutic potential of VIP and PACAP analogs in high-risk neuroblastoma.
- To examine the effects of these neuropeptides on MYCN expression, ALK signaling, and cell invasion in NB cell lines.
Main Methods:
- Studied VIP and PACAP analogs in MYCN-amplified NB cell lines (SK-N-DZ, IMR-32) and ALK-mutated Kelly cells.
- Assessed effects on neuritogenesis, MYCN expression, AKT activity, and cell invasion.
- Analyzed expression of VIP/PACAP receptors (VPAC1, VPAC2, PAC1).
Main Results:
- VIP induced neuritogenesis and reduced MYCN expression and invasion in specific NB cell lines.
- VIP decreased AKT activity in ALK-mutated cells, with PKA-dependent effects.
- [Hyp(2)]PACAP-27 demonstrated higher efficacy than VIP in Kelly cells.
- All tested NB cell lines expressed VPAC1, VPAC2, and PAC1 receptor genes.
Conclusions:
- VIP and PACAP analogs exhibit potential for reducing the aggressiveness of high-risk neuroblastoma.
- These neuropeptides modulate key molecular targets and cellular processes relevant to NB therapy.
- Further research into VIP and PACAP analogs could lead to new therapeutic strategies for pediatric cancer.
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