Metabotropic glutamate receptors as a new therapeutic target for malignant gliomas

Abstract

Metabotropic glutamate receptors (mGluR) are predominantly involved in maintenance of cellular homeostasis of central nervous system. However, evidences have suggested other roles of mGluR in human tumors. Aberrant mGluR signaling has been shown to participate in transformation and maintenance of various cancer types, including malignant brain tumors. This review intends to summarize recent findings regarding the involvement of mGluR-mediated intracellular signaling pathways in progression, aggressiveness, and recurrence of malignant gliomas, mainly glioblastomas (GBM), highlighting the potential therapeutic applications of mGluR ligands. In addition to the growing number of studies reporting mGluR gene or protein expression in glioma samples (resections, lineages, and primary cultures), pharmacological blockade in vitro of mGluR1 and mGluR3 by selective ligands has been shown to be anti-proliferative and anti-migratory, decreasing activation of MAPK and PI3K pathways. In addition, mGluR3 antagonists promoted astroglial differentiation of GBM cells and also enabled cytotoxic action of temozolomide (TMZ). mGluR3-dependent TMZ toxicity was supported by increasing levels of MGMT transcripts through an intracellular signaling pathway that sequentially involves PI3K and NF-?B. Further, continuous pharmacological blockade of mGluR1 and mGluR3 have been shown to reduced growth of GBM tumor in two independent in vivo xenograft models. In parallel, low levels of mGluR3 mRNA in GBM resections may be a predictor for long survival rate of patients. Since several Phase I, II and III clinical trials are being performed using group I and II mGluR modulators, there is a strong scientifically-based rationale for testing mGluR antagonists as an adjuvant therapy for malignant brain tumors.

ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior

“…Given connection between eIF2α and neurological/ neuropsychiatric disease 71,72 , it is foreseeable that this signaling mechanism may further contribute to the phenotypes seen in Elfn2 KO mice. Although group III mGluRs have been implicated in a variety of cancers 73,74 , it is unclear whether this transcomplex is unique or complimentary to the recently suggested role of ELFN2 in oncogenesis.…”

Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies

“…256 Glutamate metabotropic and ionotropic receptors in cancer Glutamate (Glu), a paradigmatic excitatory neurotransmitter in the mammalian brain, is tightly controlled to prevent neuronal death due to excitotoxicity. Altered glutamatergic signaling has been linked to several neurodegenerative diseases and disorders, as well as oncogenic and metastatic processes in glioma (the most common type of primary brain tumors), such as glioblastoma, the most frequent and lethal cancer of the central nervous system; 257 among other cancer types. 258 Increased glutamate levels occur in glioma and astrocytomas (Fig.…”

“…258,259 Although high levels of extracellular glutamate are toxic for normal neurons; this neurotransmitter has neurotrophic effects in GBM. 257 Glutamate is the natural agonist of ionotropic (iGluRs, which are ion channels) and metabotropic (mGluRs, G proteincoupled) receptors. The first group includes: N-methyl-D-aspartate receptors (NMDAR), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), and kainate receptors (KAR); the second is composed by eight G protein-coupled receptors (mGluR1, R2, R3, and R5 are Gq protein-coupled; while mGluR4, R6, R7, and R8 are coupled to heterotrimeric Gi proteins).…”

Proline oxidase controls proline, glutamate, and glutamine cellular concentrations in a U87 glioblastoma cell line

“…As glutamate is the main excitatory neurotransmitter in mammalian CNS, its extracellular concentrations are maintained in the low micromolar range. Glioma cells release large amounts of glutamate (see above), resulting in excitotoxicity through NMDA receptor activation which is believed to be the responsible for induced neuronal death in glioma surroundings [ 38 – 39 ], a process facilitating tumor expansion and invasion [ 34 , 40 , 41 ]. A growing number of studies report alterations in expression of metabotropic glutamate receptors in glioma samples.…”