Neuropeptide Y/Y5 Receptor Pathway Stimulates Neuroblastoma Cell Motility Through RhoA Activation.

Nouran Abualsaud,Ewa Krawczyk,Joanna Kitlinska,Lamia Alamri,Lindsay Caprio,Shiya Zhu,Susana Galli,G Ian Gallicano

doi:10.3389/fcell.2020.627090

Abstract

Neuropeptide Y (NPY) has been implicated in the regulation of cellular motility under various physiological and pathological conditions, including cancer dissemination. Yet, the exact signaling pathways leading to these effects remain unknown. In a pediatric malignancy, neuroblastoma (NB), high NPY release from tumor tissue associates with metastatic disease. Here, we have shown that NPY stimulates NB cell motility and invasiveness and acts as a chemotactic factor for NB cells. We have also identified the Y5 receptor (Y5R) as the main NPY receptor mediating these actions. In NB tissues and cell cultures, Y5R is highly expressed in migratory cells and accumulates in regions of high RhoA activity and dynamic cytoskeleton remodeling. Y5R stimulation activates RhoA and results in Y5R/RhoA-GTP interactions, as shown by pull-down and proximity ligation assays, respectively. This is the first demonstration of the role for the NPY/Y5R axis in RhoA activation and the subsequent cytoskeleton remodeling facilitating cell movement. These findings implicate Y5R as a target in anti-metastatic therapies for NB and other cancers expressing this receptor.

Highlights

Neuroblastoma (NB) is a pediatric malignancy arising due to defects in sympathetic neuron differentiation (Maris, 2010; Matthay et al, 2016)
Using both NB cells and CHO-K1 cells transfected with single types of Neuropeptide Y (NPY) receptors, we have provided the first evidence for the interactions between Y5 receptor (Y5R) and RhoA and their contribution to cytoskeleton remodeling and cell migration
We propose that the NPY/Y5R/RhoA axis is an essential pathway facilitating NB cell motility and their dissemination

Summary

Introduction

Neuroblastoma (NB) is a pediatric malignancy arising due to defects in sympathetic neuron differentiation (Maris, 2010; Matthay et al, 2016). A large group of NB patients does not respond to treatment, which often leads to the secondary disease dissemination (Maris, 2010; Smith and Foster, 2018). It has been suggested that the presence of a chemoresistant NB cell population with a cancer stem cell phenotype drives metastasis and poor clinical outcomes in high-risk NB (Maris, 2010; Bahmad et al, 2019). Targeting this NB cell sub-population is critical in the treatment of the refractory disease

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