Glutamate Receptors and Glioblastoma Multiforme: An Old "Route" for New Perspectives

Lorenzo Corsi, Andrea Mescola, Andrea Alessandrini, Lorenzo Corsi, Andrea Mescola, Andrea Alessandrini

Abstract

Glioblastoma multiforme (GBM) is the most aggressive malignant tumor of the central nervous system, with poor survival in both treated and untreated patients. Recent studies began to explain the molecular pathway, comprising the dynamic structural and mechanical changes involved in GBM. In this context, some studies showed that the human glioblastoma cells release high levels of glutamate, which regulates the proliferation and survival of neuronal progenitor cells. Considering that cancer cells possess properties in common with neural progenitor cells, it is likely that the functions of glutamate receptors may affect the growth of cancer cells and, therefore, open the road to new and more targeted therapies.

Keywords: N-methyl-d-aspartate (NMDA); cell migration; focal adhesion complex (FAK); glioblastoma multiforme; glutamate receptors; mechanobiology; protein kinase B (Akt); α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA).

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
General representation of the signaling pathways involved in the antagonism of both ionotropic and metabotropic glutamate receptors in anti-cancer mediated effects. Selective metabotropic glutamate receptor 1 (mGluR1) antagonist JNJ1659685 elicited its anti-cancer activity, by decreasing cell proliferation, through the inhibition of the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, and by increasing cell differentiation through the activation of the transcription factors small mother against decapentaplegic transcription factor (Smad) 1/5/8. LY 341495, an mGluR 2/3 selective antagonist, blocks the activation of both the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2 cascade and the Akt/mammalian target of rapamycin protein (mTOR) pathway, resulting in arrest of the cell cycle and an increase in apoptosis. Talampanel, a selective negative allosteric α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) modulator, inhibits the rise of intracellular calcium concentration, and inhibits both ERK1/2 and Akt phosphorylation, slowing down the cell proliferation, and increasing cellular stiffness through the activation of focal adhesion kinase (FAK) protein. The N-methyl-d-aspartate (NMDA) antagonists, MP1 and MP2, two memantine derivative compounds, exert their antiproliferative activity by modulating Beclin-1 binding protein, which increases the autophagic processes of glioblastoma cell line.
Figure 2
Figure 2
Schematic representation of cell reorganization on soft and rigid extracellular matrix (ECM) substrates. The actomyosin II system connected to focal adhesion complexes generates intracellular contractile forces which are transmitted to the underlying substrate, following a dynamic and mutual information exchange that can lead to changes in cell motility. A soft substrate (left) entails reduced activation of integrins, not allowing the formation of stress fibers within the cell. Conversely (right), a rigid substrate promotes the integrin activation, as well as a remarkable recruitment of actin filaments, leading to a global reinforcement of the cell, thus affecting the cell migration ability.

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