Type-3 metabotropic glutamate receptors regulate chemoresistance in glioma stem cells, and their levels are inversely related to survival in patients with malignant gliomas

被引：58

作者：

Ciceroni, C. ^{[1
]}

Bonelli, M. ^{[2
]}

Mastrantoni, E. ^{[2
]}

Niccolini, C. ^{[2
]}

Laurenza, M. ^{[2
]}

Larocca, L. M. ^{[3
]}

Pallini, R. ^{[4
]}

Traficante, A. ^{[5
]}

Spinsanti, P. ^{[2
]}

Ricci-Vitiani, L. ^{[6
]}

Arcella, A. ^{[5
]}

De Maria, R. ^{[6
]}

Nicoletti, F. ^{[2
,5
]}

Battaglia, G. ^{[5
]}

Melchiorri, D. ^{[1
,2
]}

机构：

[1] IRCCS San Raffaele Pisana, I-00163 Rome, Italy

[2] Univ Roma La Sapienza, Dept Physiol & Pharmacol, I-00185 Rome, Italy

[3] Univ Cattolica Sacro Cuore, Inst Pathol, I-00186 Rome, Italy

[4] Univ Cattolica Sacro Cuore, Inst Neurosurg, I-00186 Rome, Italy

[5] IRCCS Neuromed, I-86077 Pozzilli, Italy

[6] Ist Super Sanita, Dept Hematol, I-00161 Rome, Italy

来源：

CELL DEATH AND DIFFERENTIATION | 2013年 / 20卷 / 03期

关键词：

metabotropic glutamate receptor mGlu3; glioblastoma; temozolomide; cancer stem cells; MGMT; NF-KAPPA-B; GLIOBLASTOMA; MGMT; PROTEIN; METHYLTRANSFERASE; METHYLATION; REPAIR; HYPERMETHYLATION; TEMOZOLOMIDE; INHIBITION;

D O I：

10.1038/cdd.2012.150

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Drug treatment of malignant gliomas is limited by the intrinsic resistance of glioma stem cells (GSCs) to chemotherapy. GSCs isolated from human glioblastoma multiforme (GBM) expressed metabotropic glutamate receptors (mGlu3 receptors). The DNA-alkylating agent, temozolomide, killed GSCs only if mGlu3 receptors were knocked down or pharmacologically inhibited. In contrast, mGlu3 receptor blockade did not affect the action of paclitaxel, etoposide, cis-platinum, and irinotecan. mGlu3 receptor blockade enabled temozolomide toxicity by inhibiting a phosphatidylinositol-3-kinase/nuclear factor-kappa B pathway that supports the expression of O-6-methylguanine-DNA methyltransferase (MGMT), an enzyme that confers resistance against DNA-alkylating agents. In mice implanted with GSCs into the brain, temozolomide combined with mGlu3 receptor blockade substantially reduced tumor growth. Finally, 87 patients with GBM undergoing surgery followed by adjuvant chemotherapy with temozolomide survived for longer time if tumor cells expressed low levels of mGlu3 receptors. In addition, the methylation state of the MGMT gene promoter in tumor extracts influenced survival only in those patients with low expression of mGlu3 receptors in the tumor. These data encourage the use of mGlu3 receptor antagonists as add-on drugs in the treatment of GBM, and suggest that the transcript of mGlu3 receptors should be measured in tumor specimens for a correct prediction of patients' survival in response to temozolomide treatment. Cell Death and Differentiation (2013) 20, 396-407; doi:10.1038/cdd.2012.150; published online 23 November 2012

引用

页码：396 / 407

页数：12

共 46 条

[21] Novel mechanism whereby nuclear factor κB mediates DNA damage repair through regulation of O6-methylguanine-DNA-methyltransferase [J].