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.