Affiliations: Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Belgium | Department of Physiology and Pharmacology, Catholic University of Louvain (UCL), Brussels, Belgium | Unibioscreen S.A., Brussels, Belgium | Digestive Health Center, University of Virginia Health System, Charlottesville, USA
Note: [] Corresponding author: Robert Kiss, Laboratory of Toxicology, Institute of Pharmacy, Free University of Brussels (ULB), Campus de la Plaine CP205/1, Boulevard du Triomphe, 1050 Brussels, Belgium. Tel.: +32 477 62 20 83; Fax: +322 332 53 35; E-mail: [email protected].
Abstract: Background: While the neurotensin (NT) roles in pancreatic cancer growth are well documented, its effects on pancreatic cancer cell migration have not been described. Methods: The NT-induced effects on the migration process of human pancreatic ductal adenocarcinoma cells (PDACs) were characterized by means of various assays including computer-assisted video-microscopy, fluorescence microscopy, ELISA-based, small GTPase pull-down and phosphorylation assays. Results: The NT-induced modifications on in vitro PDACs migration largely depended on the extra-cellular matrix environment and cell propensity to migrate collectively or individually. While NT significantly reduced the level of migration of collectively migrating PDACs on vitronectin, it significantly increased the level of individually migrating PDACs. These effects were mainly mediated through the sortilin/NTR3 receptor. Neurotensin both induced altered expression of αV and β5 integrin subunits in PDACs cultured on vitronectin resulting in modified adhesion abilities, and caused modifications to the organization of the actin cytoskeleton through the NT-mediated activation of small Rho GTPases. While the NT effects on individually migrating PDACs were mediated at least through the EGFR/ERK signaling pathways, those on collectively migrating PDACs appeared highly dependent on the PI 3-kinase pathway. Conclusion: This study strongly suggests the involvement of neurotensin in the modulation of human PDAC migration.
