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Neurotensin activates rac1 and cdc42, but not rhoa, in human U373 glioblastoma cells, and modifies their migratory patterns

par Servotte, S;Camby, Isabelle ;Debeir, Olivier ;Deroanne, Christophe;Lapière, C M;Kiss, Robert ;Nusgens, B;Decaestecker, Christine
Référence Cell migration in cancer and immunity: Joint BSCDB-BIS meeting(27-28 May 2005: Brussels), Cell migration in cancer and immunity, Join Spring Meeting of the BSCBD and the BIS, page (18)
Publication Publié, 2005-05-27

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Résumé :

Astrocytic tumors are associated with dismal prognoses due to their pronounced ability to diffusely invade the brain parenchyma (Lefranc et al., J Clin Oncol 2005). Various neuropeptides display a large number of functions in the central and peripheral nervous system. Gastrin has already been shown to affect both cell proliferation and migration (Camby et al., J Natl Cancer Inst 1996; DeHauwer et al., J Neurobiol 1998; Lefranc et al., Lab Invest 2002) in human experimental gliomas. While we already suggested a role for neurotensin in glioma cell proliferation (Camby et al., Neuropeptide 1996), its action on glioma cell migration has never been investigated. Therefore, the present study aims at analyzing the neurotensin-induced alterations of the migratory patterns of human U373 glioblastoma cells. Most of the neuropeptides displaying physiological roles in the brain act through their binding to specific G-protein-coupled-receptors (GPCRs) on the surface of their target cells. Once a neuropeptide binds to its GPCR(s), it can induce profound changes in the organization of the actin cytoskeleton which is a major actor in the cell migration process (Rozengurt and Walsch, Annu Rev Physiol 2001). Three subtypes of neurotensin receptors have been cloned. While NT-R1 and NT-R2 belong to the GPCR family, NT-R3 is a new type of neuropeptide receptor which is a 95 kDa protein (identical to gp95/sortilin) with a single transmembrane domain. RT-PCR analyses evidenced that U373 tumor cells express mRNAs for NT-R1, -R2 and -R3. Treating U373 cells with 10 nM neurotensin markedly modified their morphological patterns as well as the organization of their actin cytoskeleton. The family of the Rho-GTPase proteins plays a pivotal role in regulating the actin cytoskeleton organization. While RhoA regulates the assembly of contractile actin-myosin filaments, Rac1 and Cdc42 regulate actin polymerization to form peripheral lamellipodial and filopodial protrusions respectively. Pull-down assays revealed that neurotensin induced a dose-dependent activation in U373 cells of both Rac1 and Cdc42, and, to a lesser extent, RhoA. By using a scratch wound assay, we observed that 0.1 and 10 nM neurotensin very significantly decreased the ability of U373 glioblastoma cells to migrate and colonize the wound (in the absence of fetal calf serum). Computer-assisted phase-contrast microscope analyses showed that neurotensin decreases the motility levels of U373 glioblastoma cells cultured on uncoated flasks (plastic). In sharp contrast, neurotensin stimulates the motility of U373 cells cultured on laminin (a pro-adhesive extracellular matrix component ubiquitously secreted by glioma cells, known for stimulating their migration in vitro and upregulated in high-grade astrocytic tumors). In conclusion, our data strongly suggest that neurotensin, in addition to gastrin, is a neuropeptide able to modulate tumor astrocyte migration into the brain parenchyma.