Metabotropic glutamate receptors as a new therapeutic target for malignant gliomas.

Mery Stefani Leivas Pereira,Chairini Cássia Thomé,Paulo Valdeci Worm,Diogo Losch De Oliveira,Fábio Klamt

doi:10.18632/oncotarget.15299

Mery Stefani Leivas Pereira, Chairini Cássia Thomé + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.15299

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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.

Highlights

Gliomas are the most common type of primary brain tumor and are often fast growing with a poor prognosis for patient [1]
In United States, GBM accounts for 15.1% of all primary brain tumors, 46.1% of primary malignant brain tumors, and its annual incidence is 3.2 per 100,000 people [6]
Cultures exposed to mGluR3 antagonist LY 341495 (100 nM) enhanced Smad1/5/8 phosphorylation to an extent similar to BMP4. These results suggested that activation of mGluR3 could inhibit BMP4 receptor signaling by activation of MAPK pathway

Summary

Introduction

Gliomas are the most common type of primary brain tumor and are often fast growing with a poor prognosis for patient [1]. In another study, using primary cultures from human GBM biopsies, D’Onofrio et al (2003) showed www.impactjournals.com/oncotarget pharmacological blockade of mGluR3 reduced cell proliferation [68].

Results

Conclusion