Abstract
Glioblastoma (GBM) remains an incurable disease, mainly due to the high migration and invasion potency of GBM cells inside the brain. PI3K/Akt, Sonic Hedgehog (SHH), and PKA pathways play major regulatory roles in the progression of GBM. The vasoactive intestinal peptide (VIP) family of neuropeptides and their receptors, referred in this article as the “VIP-receptor system”, has been reported to regulate proliferation, differentiation, and migration in a number of tumor cell types and more particularly in GBM cells. These neuropeptides are potent activators of the cAMP/PKA pathway. The present study aimed to investigate the cross-talks between the above cited signaling cascades. Regulation by VIP-related neuropeptides of GBM migration and invasion was evaluated ex vivo in rat brain slices explanted in culture. Effects of different combinations of VIP-related neuropeptides and of pharmacological and siRNA inhibitors of PKA, Akt, and of the SHH/GLI1 pathways were tested on GBM migration rat C6 and human U87 GBM cell lines using the wound-healing technique. Quantification of nuclear GLI1, phospho-Akt, and phospho-PTEN was assessed by western-immunoblotting. The VIP-receptor system agonists VIP and PACAP-38 significantly reduced C6 cells invasion in the rat brain parenchyma ex vivo, and C6 and U87 migration in vitro. A VIP-receptor system antagonist, VIP10-28 increased C6 cell invasion in the rat brain parenchyma ex vivo, and C6 and migration in vitro. These effects on cell migration were abolished by selective inhibitors of the PI3K/Akt and of the SHH pathways. Furthermore, VIP and PACAP-38 reduced the expression of nuclear GLI1 while VIP10-28 increased this expression. Selective inhibitors of Akt and PKA abolished VIP, PACAP-38, and VIP10-28 effects on nuclear GLI1 expression in C6 cells. PACAP-38 induced a time-dependent inhibition of phospho-Akt expression and an increased phosphorylation of PTEN in C6 cells. All together, these data indicate that triggering the VIP-receptor system reduces migration and invasion in GBM cells through a PKA-dependent blockade of the PI3K/Akt and of the SHH/GLI1 pathways. Therefore, the VIP-receptor system displays anti-oncogenic properties in GBM cells and PKA is a central core in this process.
Highlights
Glioblastoma multiforme (GBM) are the most frequent and malignant adult brain cancers.Their origin remains unclear, but it has been proposed that they could develop from the transformation of poorly differentiated glial progenitors or of neural stem cells [1,2,3,4]
Analysis by RT-qPCR of mRNA expression of the components of the vasoactive intestinal peptide (VIP)-receptor system reveals that C6 cells mainly express VIP and the VPAC2 receptor and very limited levels of PACAP, VPAC1 and PAC1 mRNAs
Ex vivo invasion assays on rat brain slices were performed in order to assess the potential action of VIP and related peptides on this process in rat C6 GBM cells
Summary
Glioblastoma multiforme (GBM) are the most frequent and malignant adult brain cancers Their origin remains unclear, but it has been proposed that they could develop from the transformation of poorly differentiated glial progenitors or of neural stem cells [1,2,3,4]. In spite of constant progress of neurosurgical resection, radio- and chemotherapy, GBM remains an incurable disease with a median survival time less than two years after diagnosis. This is the consequence of the high migration and invasion potency of GBM cells, more of the subset of so-called GBM stem cells or GSCs [6]
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