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

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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.

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Acknowledgements

We thank Mme Marie-Thérèse Schouft for her expertise in cytometry, the PRIMACEN platform (University of Rouen, France) for imaging equipments and Mr Arnaud Arabo and Mrs Huguette Lemonnier for skillful technical assistance. This work was supported by a CIHR (Canadian Institutes of Health Research) grant to RL and by Inserm, Géfluc, TC2N network, LARC Neuroscience and Institute on Innovative and Biomedical Research (IRIB), The University of Rouen. CL, VL, J-EJ and P-OG were recipients of a fellowship from the Haute-Normandy or French ministry.

Author Contributions

CL performed main experiments on glioma cells (cell growth assays, cell cycle analysis, apoptosis, transwell migration, adhesion, immunohistochemistry, western blotting, ELISA). LD participated in western blotting and ELISA experiments, J-EJ validated and tested the UTERY(AAA) mutant on cell adhesion assay and VL validated the migration assay. P-OG performed immunohistochemical experiments on glioblastoma tissue biopsies. CB, NP, LP and RL provided background and experiments on BRET and FRET-HTRF biotechnologies; AL and FP provided glioblastoma biopsies from the Haute-Normandie tumorothèque; and PG, FM and HC supervised the study. HC and CL wrote the paper.

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Lecointre, C., Desrues, L., Joubert, J. et al. Signaling switch of the urotensin II vasosactive peptide GPCR: prototypic chemotaxic mechanism in glioma. Oncogene 34, 5080–5094 (2015). https://doi.org/10.1038/onc.2014.433

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