ArticleMolecular cancer2007
O6-methylguanine-DNA methyltransferase is downregulated in transformed astrocyte cells: implications for anti-glioma therapies.
Article in Molecular cancer, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 46 citations in OpenAlex.
- Structure-changeable luminescent Eu(III) complex as a human cancer grade probing system for brain tumor diagnosis.Scientific reports · 2024Article
- Valproic acid-induced changes of 4D nuclear morphology in astrocyte cells.Molecular biology of the cell · 2021Article
- The low doses of SWCNTs affect the expression of proliferation and apoptosis related genes in normal human astrocytes.Current research in toxicology · 2021Article
- MGMT: Immunohistochemical Detection in High-Grade Astrocytomas.Journal of neuropathology and experimental neurology · 2019Article
- Article
- The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors.Nature communications · 2017Article
- Comprehensive Glycomics of a Multistep Human Brain Tumor Model Reveals Specific Glycosylation Patterns Related to Malignancy.PloS one · 2015Article
- Progression of O⁶-methylguanine-DNA methyltransferase and temozolomide resistance in cancer research.Molecular biology reports · 2014Review
- Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.Nature genetics · 2014Article
- High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor.BMC cancer · 2013Article
- Valproic acid sensitizes human glioma cells for temozolomide and γ-radiation.Journal of neuro-oncology · 2012Article
- Comprehensive analysis of MGMT promoter methylation: correlation with MGMT expression and clinical response in GBM.PloS one · 2011Article
- Analysis of an alternative human CD133 promoter reveals the implication of Ras/ERK pathway in tumor stem-like hallmarks.Molecular cancer · 2010Article
- O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients.Neuro-oncology · 2010Article
- Interleukin-24 overcomes temozolomide resistance and enhances cell death by down-regulation of O6-methylguanine-DNA methyltransferase in human melanoma cells.Molecular cancer therapeutics · 2008Article
- Nonsteroidal anti-inflammatory drug-activated gene (NAG-1/GDF15) expression is increased by the histone deacetylase inhibitor trichostatin A.The Journal of biological chemistry · 2008Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundA novel alkylating agent, temozolomide, has proven efficacious in the treatment of malignant gliomas. However, expression of O6-methylguanine-DNA methyltransferase (MGMT) renders glioma cells resistant to the treatment, indicating that identification of mechanisms underlying the gene regulation of MGMT is highly required. Although glioma-derived cell lines have been widely employed to understand such mechanisms, those models harbor numerous unidentified genetic lesions specific for individual cell lines, which complicates the study of specific molecules and pathways.
resultsWe established glioma models by transforming normal human astrocyte cells via retroviral-mediated gene transfer of defined genetic elements and found that MGMT was downregulated in the transformed cells. Interestingly, inhibitors of DNA methylation and histone deacetylation failed to increase MGMT protein levels in the transformed astrocyte cells as well as cultured glioblastoma cell lines, whereas the treatment partially restored mRNA levels. These observations suggest that downregulation of MGMT may depend largely on cellular factors other than promoter-hypermethylation of MGMT genes, which is being used in the clinic to nominate patients for temozolomide treatment. Furthermore, we discovered that Valproic acid, one of histone deacetylase inhibitors, suppressed growth of the transformed astrocyte cells without increasing MGMT protein, suggesting that such epigenetic compounds may be used to some types of gliomas in combination with alkylating agents.
conclusionNormal human astrocyte cells allow us to generate experimental models of human gliomas by direct manipulation with defined genetic elements, in contrast to tumor-derived cell lines which harbor numerous unknown genetic abnormalities. Thus, we propose that the study using the transformed astrocyte cells would be useful for identifying the mechanisms underlying MGMT regulation in tumor and for the development of rational drug combination in glioma therapies.
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