Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

Abstract

Background: Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that mediate neuronal excitability and synaptic plasticity in the central nervous system, and emerging evidence suggests a role of mGluRs in the biology of cancer. Previous studies showed that mGluR1 was a potential therapeutic target for the treatment of breast cancer and melanoma, but its role in human glioma has not been determined. Methods: In the present study, we investigated the effects of mGluR1 inhibition in human glioma U87 cells using specific targeted small interfering RNA (siRNA) or selective antagonists Riluzole and BAY36-7620. The anti-cancer effects of mGluR1 inhibition were measured by cell viability, lactate dehydrogenase (LDH) release, TUNEL staining, cell cycle assay, cell invasion and migration assays in vitro, and also examined in a U87 xenograft model in vivo. Results: Inhibition of mGluR1 significantly decreased the cell viability but increased the LDH release in a dose-dependent fashion in U87 cells. These effects were accompanied with the induction of caspase-dependent apoptosis and G0/G1 cell cycle arrest. In addition, the results of Matrigel invasion and cell tracking assays showed that inhibition of mGluR1 apparently attenuated cell invasion and migration in U87 cells. All these anti-cancer effects were ablated by the mGluR1 agonist L-quisqualic acid. The results of western blot analysis showed that mGluR1 inhibition overtly decreased the phosphorylation of PI3K, Akt, mTOR and P70S6K, indicating the mitigated activation of PI3K/Akt/mTOR pathway. Moreover, the anti-tumor activity of mGluR1 inhibition in vivo was also demonstrated in a U87 xenograft glioma model in athymic nude mice. Conclusion: The remarkable efficiency of mGluR1 inhibition to induce cell death in U87 cells may find therapeutic application for the treatment of glioma patients.

Schisandrin B suppresses glioma cell metastasis mediated by inhibition of mTOR/MMP-9 signal pathway

“…Also, mTOR by L-Leucine reversed Schisandrin B's anti-cell metastasis action, and significantly increased number of cell migrated and invasive cell. Our finding suggested the involvement of PI3K/Akt/ mTOR cascade was in Schisandrin B's anti-metastasis and were consistent with previous researches that pointed out that resultant deregulation of the Akt/mammalian target of mTOR signaling pathway from these alterations has shown to be an important determinant of gliomagenesis [17,22].…”

Isogambogenic Acid Inhibits the Growth of Glioma Through Activation of the AMPK-mTOR Pathway

“…As is well recognized, the key role of mTOR is as a repressor of autophagy; the decrease in mTOR activity can effectively initiate the autophagic response in glioma cells [34-36]. Activation of AMPK leads to the inhibition of mTOR, which also propels autophagy [33].…”

Valproic Acid Promotes Human Glioma U87 Cells Apoptosis and Inhibits Glycogen Synthase Kinase-3β Through ERK/Akt Signaling

“…The activation of the MAPK pathway by different stimuli may lead to GSK3β inhibition [58,59,63]. In addition, as the major target of the PI3K, Akt regulates many downstream targets for the execution of its cell functions (such as cell growth and migration) [64][65][66]. Previous studies showed that Akt activation led to GSK3β phosphorylation [67,68], while others showed that lithium was able to activate PI3K and Akt and in turn to induce GSK3β phosphorylation and inactivation [69,70].…”