Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

O6-Methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation has recently emerged as a powerful determinant of chemotherapy sensitivity in glioblastomas. To adapt such an important epigenetic biomarker to routine application in the clinical setting, we validated the conventionally used methylation-specific polymerase chain reaction (MSP) assay for its relevance in the determination of MGMT methylation status. MGMT promoter hypermethylation analysis employing MSP was performed on 25 primary glioblastoma samples and 7 cell lines, and compared with the more robust direct promoter sequencing that profiled the methylation status of 27 CpG sites within the MGMT promoter. In addition, the MGMT expression at the protein level was evaluated in the primary tumor samples using immunohistochemistry and in the cell lines using Western blotting analysis. Our MSP analyses yielded reproducible results, which were identical to the bisulfite sequencing data in all except one primary tumor that was negative on MSP. A poor correlation existed between the immunohistochemical staining results and the methylation status of the MGMT promoter in primary glioblastoma samples. Neither MSP-MGMT methylation nor immunohistochemical MGMT expression had prognostic implications in this small and non-uniform group of patients. In all of the cell lines with loss of MGMT expression, signals of methylated DNA were detected by MSP. Our data support the feasibility and reliability of MSP analysis, which could be routinely implemented in the diagnostic setting.
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PMID:Relevance of MSP assay for the detection of MGMT promoter hypermethylation in glioblastomas. 1869 75

Glioblastoma multiforme is the most common primary tumor of the central nervous system. The drug temozolomide (TMZ) prolongs lifespan in many glioblastoma patients. The sensitivity of glioblastoma cells to TMZ is interfered by many factors, such as the expression of O-6-methylguanine-DNA methyltransferase (MGMT) and activation of AKT signaling. We have recently identified the interaction between netrin-4 (NTN4) and integrin beta-4 (ITGB4), which promotes glioblastoma cell proliferation via activating AKT-mTOR signaling pathway. In the current work we have explored the effect of NTN4/ITGB4 interaction on TMZ induced glioblastoma cell senescence. We report here that the suppression of either ITGB4 or NTN4 in glioblastoma cell lines significantly enhances cellular senescence. The sensitivity of GBM cells to TMZ was primarily determined by the expression of MGMT. To omit the effect of MGMT, we concentrated on the cell lines devoid of expression of MGMT. NTN4 partially inhibited TMZ induced cell senescence and rescued AKT from dephosphorylation in U251MG cells, a cell line bearing decent levels of ITGB4. However, addition of exogenous NTN4 displayed no significant effect on TMZ induced senescence rescue or AKT activation in U87MG cells, which expressed ITGB4 at low levels. Furthermore, overexpression of ITGB4 combined with exogenous NTN4 significantly attenuated U87MG cell senescence induced by TMZ. These data suggest that NTN4 protects glioblastoma cells from TMZ induced senescence, probably via rescuing TMZ triggered ITGB4 dependent AKT dephosphorylation. This suggests that interfering the interaction between NTN4 and ITGB4 or concomitant use of the inhibitors of the AKT pathway may improve the therapeutic efficiency of TMZ.
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PMID:NETRIN-4 protects glioblastoma cells FROM temozolomide induced senescence. 2426 16

O-6-methylguanine-DNA methyltransferase (MGMT) is an abundantly expressed nuclear protein dealkylating O6-methylguanine (O6-MG) DNA residue, thus correcting the mismatches of O6-MG with a thymine residue during DNA replication. The dealkylating effect of MGMT is relevant not only in repairing DNA mismatches produced by environmental alkylating agents promoting tumor pathogenesis, but also when alkylating molecules are applied in the chemotherapy of different cancers, including glioma, the most common primary tumor of the central nervous system. Elevated MGMT gene expression is known to confer resistance to the treatment with the alkylating drug temozolomide in patients affected by gliomas and, on the contrary, methylation of MGMT gene promoter, which causes reduction of MGMT protein expression, is known to predict a favourable response to temozolomide. Thus, detecting expression levels of MGMT gene is crucial to indicate the option of alkylating agents or to select patients directly for a second line targeted therapy. Further study is required to gain insights into MGMT expression regulation, that has attracted growing interest recently in MGMT promoter methylation, histone acetylation and microRNAs expression. The review will focus on the epigenetic regulation of MGMT gene, with translational applications to the identification of biomarkers predicting response to therapy and prognosis.
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PMID:Regulation of expression of O6-methylguanine-DNA methyltransferase and the treatment of glioblastoma (Review). 2603 92