Is MGMT inducible in malignant glioma cells?

First-line chemotherapeutics for malignant gliomas are alkylating agents, which have methylating (temozolomide) and chloroethylating (BCNU, CCNU, ACNU, fotemustine) properties. These drugs induce a plethora of DNA adducts from which the minor adducts O6-methylguanine and O6-chloroethylguanine are the main toxic one. These DNA lesions are repaired by the suicide enzyme O⁶-methylguanine-DNA methyltransferase (MGMT), which transferes the alkyl group to an own cysteine residue, thereby restoring guanine in the DNA and thus preventing from cell death. MGMT is not expressed in 17% of primary glioblastomas on enzyme level. This fraction gets lost in the first recurrencies, indicating upregulation of MGMT during therapy. MGMT is strongly regulated epigenetically by gene silencing, and promoter methylation also declined during cancer therapy, which may contribute to the observed reactivation of MGMT in gliomas. Since MGMT is inducible by genotoxic stress and glucocorticoids on gene and protein level in rodents (e.g. in rat and mice liver) the question arises whether MGMT can be upregulated following therapy in human cells, notably in gliomas. Here, data will be reviewed from our own lab and others regarding MGMT regulation on gene level. We have cloned the MGMT promoter and have shown that a) the basic activity of the cloned promoter does not correspond with the endogenous cellular MGMT mRNA, protein and activity in glioma cells; b) the transfected MGMT promoter is inducible by dexamethason, TPA and resveratrol, but not following treatment with the alkylating agents temozolomide and nimustine and also not by ionizing irradiation; c) induction of endogenous MGMT was not observed following these treatments; d) the endogenous MGMT level weakly inversely correlates with the miRNA 181 d. The available data indicate that MGMT is not extensively induced on transcriptional level during radiation and TMZ based cancer therapy. They also support a role of miRNA in regulation of the expression level. Work was supported by DFG KA724.

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