Neuropeptides of the VIP family inhibit glioblastoma cell invasion
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Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are neuropeptides acting through VPAC1, VPAC2 and PAC1 receptors (referred here as the VIP-receptor system). In the central nervous system, VIP and PACAP are involved in neurogenesis, cell differentiation and migration, suggesting that they could be implicated in the development of glioblastoma (GBM). The infiltrative nature of GBM remains a major problem for the therapy of these tumors. We previously demonstrated that the VIP-receptor system regulated cell migration of the human cell lines M059J and M059K, derived from a single human GBM. Here, we evaluated the involvement of the VIP-receptor system in GBM cell invasion. In Matrigel invasion assays, M059K cells that express more the VIP-receptor system than M059J cells were less invasive. Invasion assays performed in the presence of agonists, antagonists or anti-PACAP antibodies as well as experiments with transfected M059J cells overexpressing the VPAC1 receptor indicated that the more the VIP-receptor system was expressed and activated, the less the cells were able to invade. Western immunoblotting experiments revealed that the VIP-receptor system inactivated the signaling protein AKT. Invasion assays carried out in the presence of an AKT inhibitor demonstrated the involvement of this signaling kinase in the regulation of cell invasion by the VIP-receptor system in M059K cells. The inhibition by VIP of invasion and AKT was also observed in U87 cells. In conclusion, VIP and PACAP act as anti-invasive factors in different GBM cell lines, a function mediated by VPAC1 inhibition of AKT signaling in M059K cells.
KeywordsVIP PACAP Glioblastoma Cell invasion VPAC1 AKT
We thank Marianne Bernard for her help in the preparation of plasmid stocks in bacteria and Pr L. Karayan, Université de Poitiers, who kindly provided the M059J and M059K cells. This work was supported by grants from the ‘‘Institut National du Cancer (INCA), Cancéropôle Grand-Ouest”, from the ‘‘Ligue contre le Cancer du Grand-Ouest, comité de la Vienne et comité des Deux-Sèvres” and from the “Lions Club de Melle”. Stéphanie Cochaud and Souheyla Bensalma were recipients of Ph.D. fellowships from the French ‘‘Ministère de l’enseignement supérieur et de la recherche” and from the « Région Poitou–Charentes», respectively.
Conflict of interest
The authors declare that they have no conflict of interest.
- 4.Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, Vaudry D, Vaudry H, Waschek JA, Said SI (2012) Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol 166:4–17CrossRefPubMedCentralPubMedGoogle Scholar
- 6.Reubi JC (1995) In vitro identification of vasoactive intestinal peptide receptors in human tumors: implications for tumor imaging. J Nucl Med Off Publ Soc Nucl Med 36:1846–1853Google Scholar
- 27.May V, Lutz E, MacKenzie C, Schutz KC, Dozark K, Braas KM (2010) Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1HOP1 receptor activation coordinates multiple neurotrophic signaling pathways: Akt activation through phosphatidylinositol 3-kinase gamma and vesicle endocytosis for neuronal survival. J Biol Chem 285:9749–9761CrossRefPubMedCentralPubMedGoogle Scholar
- 28.Mei FC, Qiao J, Tsygankova OM, Meinkoth JL, Quilliam LA, Cheng X (2002) Differential signaling of cyclic AMP: opposing effects of exchange protein directly activated by cyclic AMP and cAMP-dependent protein kinase on protein kinase B activation. J Biol Chem 277:11497–11504CrossRefPubMedGoogle Scholar