Transcriptional modulation of calcium‐permeable AMPA receptor subunits in glioblastoma by MEK–ERK1/2 inhibitors and their role in invasion

Abstract

Glioblastoma is the most common primary brain tumor. Glioblastoma cells secrete a significant amount of glutamate, which serve as a potential growth factor in glioma pathobiology through their specific receptor subtypes including α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR). Glioblastoma express AMPAR subunits; however, its regulation and activation with downstream intracellular signaling are not well‐understood. Phosphorylated‐extracellular signaling‐regulated kinase (ERK)1/2 is known to regulate the ionotropic glutamate receptors in cortical neurons. The mitogen‐activated protein kinase cascade is frequently activated in several tumors, including glioma. Nonetheless, the association of ERK signaling with AMPAR subunits in glioblastoma is undetermined. Here, we demonstrated potential role of AMPAR in invasion, and the modulation of AMPAR subunits at transcript level by ERK signaling in glioblastoma cells. Inhibition of ERK signaling specifically downregulated the expression of calcium‐permeable AMPAR subunits, GluA1 and GluA4, and upregulated calcium‐impermeable AMPAR subunit GluA2 implying differential regulation of the expression of calcium‐permeable AMPAR subunits of glioblastoma. Concomitantly, it significantly decreased the invasion of U87MG cells. Taken together, these findings suggest that the AMPAR enhances invasion of glioblastoma, and ERK signaling modulates the differential expression of calcium‐permeable AMPAR phenotype that might play a crucial role in the invasive propensity of glioblastoma cells.

The role of glutamate receptors in the regulation of the tumor microenvironment

“…The inhibition of AMPAR using the non-competitive antagonist CNQX decreased the tumor cell-cytotoxic effects caused by the increase in Ca 2+ influx indicating the protective role played by AMPAR inhibition in this process ( 38 ). The increase in Ca 2+ influx is mediated by the calcium-permeable AMPAR-type glutamate receptors assembled from the GluR1 and/or GluR4 subunits ( 109 ). It is important to consider the subunit in the biology of AMPAR because, in contrast to GluR1 and GluR4 which are calcium-permeable, the GluR2 subunit is calcium-impermeable AMPA receptors.…”

“…It is important to consider the subunit in the biology of AMPAR because, in contrast to GluR1 and GluR4 which are calcium-permeable, the GluR2 subunit is calcium-impermeable AMPA receptors. In glioblastoma, the aggressive growth of glioma cells was also correlated with the increase in Ca 2+ influx and the activation of AMPAR, whereas the inhibition of AMPAR by the antagonist suppressed the growth of glioma cells and decreased the invasiveness of the tumor, indicating the direct involvement of AMPAR in the increased in tumor growth ( 109 ). The cooperation between the calcium-permeable AMPAR-type glutamate receptors and ERK–MAPK is necessary for the AMPAR to induce the growth of tumor cells ( Figure 3 ).…”

“…The previous study has also revealed, that in high-grade glioma cells, aggressiveness is correlated with the significant phosphorylation of ERK compared to low-grade gliomas, indicating that ERK is involved in the aggressive phenotype of glioma cells ( 111 ). Moreover, the inhibition of ERK-MAPK resulted in the reduction of the aggressiveness of glioma cells ( Figure 3 ) ( 109 ).…”

Combining a noble gas with radiotherapy: Glutamate receptor antagonist xenon acts as a radiosensitizer in glioblastoma

“…The excitatory neurotransmitter glutamate and ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) play a key role in neuron-glioma interaction, where glioma cells receive glutamate through unidirectional synaptic connections (1,3,5). In addition, glioma cells have been shown to secret large amounts of glutamate in their surroundings acting as an autocrine growth stimulant through AMPARs and N-methyl-D-aspartate receptors (NMDAR), as well as exhibiting toxic effects on adjacent brain tissue and, thus, facilitating tumor invasion (6)(7)(8)(9)(10)(11).…”

Strengthening Anti-Glioblastoma Effect by Multi-Branched Dendrimers Design of a Scorpion Venom Tetrapeptide

“…Thus, complex mechanisms contribute to the development of GBM, involving multiple factors and cellular elements such as the angiogenic factors, metalloproteinases, integrins, ionic channels [ 4 ], as well as calcium receptors [ 7 , 8 ]. Calcium acts as a second messenger in many molecular mechanisms, and its intracellular rate directly influences glioblastoma cell proliferation and migration [ 9 , 10 ]. Thus, targeting these key cell elements could destabilize tumor development.…”