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Oncogene. 2015 Sep 24;34(39):5080-94. doi: 10.1038/onc.2014.433. Epub 2015 Jan 19.

Signaling switch of the urotensin II vasosactive peptide GPCR: prototypic chemotaxic mechanism in glioma.

Author information

1
Inserm U982, Laboratory of Neuronal and Neuroendocrine Communication and Differentiation, DC2N, Astrocyte and Vascular Niche, Biomedical Research Institute (IRIB), TC2N network, University of Rouen, Mont-Saint-Aignan, France.
2
Department of Pharmacology, Institut of Pharmacology, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada.
3
IGF, Institut of Functional Genomic, CNRS UMR 5203, Inserm U661, University of Montpellier 1 and 2, Montpellier, France.
4
UMR CNRS 6214, Inserm 1083, Faculté de Médecine 3, Angers, France.
5
Service of Anatomocytopathology, CHU of Rouen, ERI28 Inserm, IRIB, Rouen, France.
6
Service of Neurosurgery, CHU of Rouen, Rouen, France.

Abstract

Multiform glioblastomas (GBM) are the most frequent and aggressive primary brain tumors in adults. The poor prognosis is due to neo-angiogenesis and cellular invasion, processes that require complex chemotaxic mechanisms involving motility, migration and adhesion. Understanding these different cellular events implies identifying receptors and transduction pathways that lead to and promote either migration or adhesion. Here we establish that glioma express the vasoactive peptide urotensin II (UII) and its receptor UT and that UT-mediated signaling cascades are involved in glioma cell migration and adhesion. Components of the urotensinergic systems, UII and UT, are widely expressed in patient-derived GBM tissue sections, glioma cell lines and fresh biopsy explants. Interestingly, gradient concentrations of UII produced chemoattracting migratory/motility effects in glioma as well as HEK293 cells expressing human UT. These effects mainly involved the G13/Rho/rho kinase pathway while partially requiring Gi/o/PI3K components. In contrast, we observed that homogeneous concentrations of UII drastically blocked cell motility and stimulated cell-matrix adhesions through a UT/Gi/o signaling cascade, partially involving phosphatidylinositol-3 kinase. Finally, we provide evidence that, in glioma cells, homogeneous concentration of UII allowed translocation of Gα13 to the UT receptor at the plasma membrane and increased actin stress fibers, lamellipodia formation and vinculin-stained focal adhesions. UII also provoked a re-localization of UT precoupled to Gαi in filipodia and initiated integrin-stained focal points. Altogether, these findings suggest that UT behaves as a chemotaxic receptor, relaying a signaling switch between directional migration and cell adhesion under gradient or homogeneous concentrations, thereby redefining sequential mechanisms affecting tumor cells during glioma invasion. Taken together, our results allow us to propose a model in order to improve the design of compounds that demonstrate signaling bias for therapies that target specifically the Gi/o signaling pathway.

PMID:
25597409
DOI:
10.1038/onc.2014.433
[Indexed for MEDLINE]

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