Impairement of HT29 Cancer Cells Cohesion by the Soluble Form of Neurotensin Receptor-3.

Fabienne Massa,Christelle Devader,Sophie Béraud-Dufour,Jean Mazella,Sandra Lacas-Gervais,Thierry Coppola

doi:10.18632/genesandcancer.22

Fabienne Massa, Christelle Devader + Show 4 more

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https://doi.org/10.18632/genesandcancer.22

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Abstract

The neurotensin (NT) receptor-3 (NTSR3), also called sortilin is a multifunctional protein localized at the intracellular and plasma membrane level. The extracellular domain of NTSR3 (sNTSR3) is released by shedding from several cell lines including colonic cancer cells. This soluble protein acts as an active ligand through its ability to bind, to be internalized in the human adenocarcinoma epithelial HT29 cells and to stimulate the PI3 kinase pathway. The aim of this study was to investigate cellular responses induced by sNTSR3 in HT29 cells. The cellular functions of sNTSR3 were monitored by immunofluocytochemistry, electron microscopy and quantitative PCR in order to characterize the cell shape and the expression of adhesion proteins. We evidenced that sNTSR3 significantly regulates the cellular morphology as well as the cell-cell and the cell-matrix adherens properties by decreasing the expession of several integrins and by modifying the structure of desmosomes. Altogether, these properties lead to an increase of cell detachment upon sNTSR3 treatment on HT29, HCT116 and SW620 cancer cells. Our results indicate that sNTSR3 may induce the first phase of a process which weaken HT29 epithelial properties including desmosome architecture, cell spreading, and initiation of cell separation, all events which could be responsible for cancer metastasis.

Highlights

Numerous extracellular molecules are involved in the activation of gastrointestinal cancer tissues growth
The size of HT29 cells was assessed by counting the number of cells per 1000 μm2 which varied from 5.1 ± 0.2 cells in the absence of sNTSR3 to 4.2 ± 0.17 cells in the presence of 10 nM sNTSR3 for 30 min (Fig. 1F) (n = 25, p
neurotensin (NT) receptor-3 (NTSR3)/sortilin exerts intracellular functions to sort for examples the two-pore potassium channel TREK-1 to the plasma membrane [23], the sphingolipid activator proteins to lysosomes [24] and the brain-derived neurotrophic factor to the regulated secretion [25]

Summary

Introduction

Numerous extracellular molecules are involved in the activation of gastrointestinal cancer tissues growth Among these effectors, several neuropeptides are known to act as growth factors through their receptors which are often overexpressed in tumors [1]. Several neuropeptides are known to act as growth factors through their receptors which are often overexpressed in tumors [1] These neuropeptidergic systems are targeted for diagnosis and therapy by tools designed to modulate receptors activities [2]. EGFR ligands are transmembrane proteins that can be cleaved by matrix metalloproteases (MMPs) and released in the extracellular medium to act on their receptors [4] Another family of proteins has been recently shown to be shedded by similar mechanisms. The roles of the proteins from the Vps10p family are already known to be multiple and complex, and concern their functions as receptors or co-receptors and their involvement in the sorting of proteins to lysosomes or to the plasma membrane (for review, see [9])

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