Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) through the binding of vasoactive intestinal peptide receptors (VIPRs), perform a wide variety of effects in human cancers, including glioblastoma multiforme (GBM). This tumor is characterized by extensive areas of hypoxia, which triggers the expression of hypoxia-inducible factors (HIFs). HIFs not only mediate angiogenesis but also tumor cell migration and invasion. Furthermore, HIFs activation is linked to epidermal growth factor receptor (EGFR) overexpression. Previous studies have shown that VIP interferes with the invasive nature of gliomas by regulating cell migration. However, the role of VIP family members in GBM infiltration under low oxygen tension has not been clarified yet. Therefore, in the present study we have investigated, for the first time, the molecular mechanisms involved in the anti-invasive effect of PACAP or VIP in U87MG glioblastoma cells exposed to hypoxia induced by treatment with desferrioxamine (DFX). The results suggest that either PACAP or VIP exert an anti-infiltrative effect under low oxygen tension by modulating HIFs and EGFR expression, key elements involved in cell migration and angiogenesis. These peptides act through the inhibition of PI3K/Akt and MAPK/ERK signaling pathways, which are known to have a crucial role in HIFs regulation.
Highlights
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) belong to a family of polypeptides, comprising peptide histidine-methionine (PHM), secretin, glucagon, glucagon-like peptide (GLP), glucose-dependent insulinotropic polypeptide (GIP), growth hormone releasing hormone (GHRH), and helodermin (Sherwood et al, 2000)
Considering the relevance of the hypoxic microenvironment in determining tumor aggressivity, in the present study we investigated the effect of these peptides in the modulation of hypoxia-inducible factors (HIFs) and epidermal growth factor receptor (EGFR) expression, both key elements involved in cell migration and angiogenesis
Here, we found that the precursor proteins of PACAP and VIP, and vasoactive intestinal peptide receptors (VIPRs) are expressed in glioblastoma multiforme (GBM); precursor peptides levels seemed to be lower as compared to their receptors (Figure 1A)
Summary
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) belong to a family of polypeptides, comprising peptide histidine-methionine (PHM), secretin, glucagon, glucagon-like peptide (GLP), glucose-dependent insulinotropic polypeptide (GIP), growth hormone releasing hormone (GHRH), and helodermin (Sherwood et al, 2000) They have sequence homology and explicate their functions by binding to vasoactive intestinal peptide receptors (VIPRs) including PAC1, VPAC1, and VPAC2 receptors. Pituitary adenylate cyclase-activating polypeptide and VIP perform a regulatory role as neurotransmitters and/or neuromodulators in the peripheral and central nervous system (CNS) They are involved in different biological processes such as neuronal survival, stress response, cell division, neuro-, and glio-protective actions (Cavallaro et al, 1995; Canonico et al, 1996; D’Agata et al, 1996; D’Agata and Cavallaro, 1998; Jaworski, 2000; Castorina et al, 2008, 2010a, 2014; Giunta et al, 2012). In some instances, PACAP and VIP stimulate tumor mass growth whereas in others they show antiproliferative effect (Castorina et al, 2008, 2012; Giunta et al, 2010; D’Amico et al, 2013)
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