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Objective Metabotropic glutamate receptors(mG luR)are predominantly involved in maintenance of cellular homeostasis of central nervous system.However,evidences have suggested other roles of mG luR in human tumors.Aberrant mG luR 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 mG luR-mediated intracellular signaling pathways in progression,aggressiveness,and recurrence of malignant gliomas,mainly glioblastomas(GBM),highlighting the potential therapeutic applications of mG luR ligands.In addition to the growing number of studies reporting mG luR gene or protein expression in glioma samples(resections,lineages,and primary cultures),pharmacological blockade in vitro of mG luR1 and mG luR3 by selective ligands has been shown to be anti-proliferative and anti-migratory,decreasing activation of MAPK and PI3K pathways.In addition,mG luR3 antagonists promoted astroglial differentiation of GBM cells and also enabled cytotoxic action of temozolomide(TMZ).mG luR3-dependent TMZ toxicity was supported by increasing levels of MGMT transcripts through an intracellular signaling pathway that sequentially involves PI3K and NF-κB.Further,continuous pharmacological blockade of mG luR1 and mG luR3 have been shown to reduced growth of GBM tumor in two independent in vivo xenograft models.In parallel,low levels of mG luR3 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 mG luR modulators,there is a strong scientifically-based rationale for testing mG luR antagonists as an adjuvant therapy for malignant brain tumors.
Objective Metabotropic glutamate receptors (mG luR) are predominantly involved in maintenance of cellular homeostasis of central nervous system. Yet, evidences have suggested other roles of mG luR in human tumors. Aberrant mG luR 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 mG luR-mediated intracellular signaling pathways in progression, aggressiveness, and recurrence of malignant gliomas, mainly glioblastomas (GBM), highlighting the potential therapeutic applications of mG In addition to the growing number of studies reporting mG luR gene or protein expression in glioma samples (resections, lineages, and primary cultures), pharmacological blockade in vitro mG luR1 and mG luR3 by selective ligands has been shown to be anti -proliferative and anti-migratory, decreasing activation of MAPK and PI3K pathways. addition, mG lu R3 antagonists promoted astroglial differentiation of GBM cells and also enabled cytotoxic action of temozolomide (TMZ) .mG luR3-dependent TMZ toxicity was supported by increasing levels of MGMT transcripts through an intracellular signaling pathway that sequentially involves PI3K and NF-κB.Further, continuous pharmacological blockade of mG luR1 and mG luR3 have been shown to reduce growth of GBM tumor in two independent in vivo xenograft models.In parallel, low levels of mG luR3 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 mG luR modulators, there is a strong scientifically-based rationale for testing mG luR antagonists as an adjuvant therapy for malignant brain tumors.