Transcriptional control of O6 -methylguanine DNA methyltransferase expression and temozolomide resistance in glioblastoma

Journal of Neurochemistry
Caroline HappoldMichael Weller

Abstract

O6 -methylguanine DNA methyltransferase (MGMT) promoter methylation is a predictive biomarker for benefit from alkylating chemotherapy, specifically temozolomide (TMZ), in glioblastoma, the most common malignant intrinsic brain tumor. Glioma-initiating cells (GIC) with stem-like properties have been associated with resistance to therapy and progression. We assessed the levels of MGMT mRNA and MGMT protein by real-time PCR and immunoblot and evaluated the impact of MGMT on TMZ sensitivity in clonogenicity assays in GIC sphere cultures (S) or differentiated adherent monolayer cultures (M). Nuclear factor kappa B (NF-κB) signaling was assessed by reporter assay and immunoblot. Compared to M cells, S cells expressed higher levels of MGMT. Differentiation of GIC induced by S-to-M transition resulted in a gradual loss of MGMT expression and increased TMZ sensitivity. This transcriptional regulation of MGMT was restricted to cell lines without MGMT promoter methylation and was not coupled to any specific neurobasal (NB) stem cell medium supplement or loss of cell adhesion. Expression levels of p50/p65 subunits of NF-κB, a transcriptional regulator of MGMT, were increased in S cells. Inhibition of NF-κB by the small molecule inhibitor,...Continue Reading

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Citations

Jan 23, 2020·Journal of the Royal Society, Interface·Inmaculada C SorribesHarsh V Jain
Dec 24, 2018·Journal of Applied Toxicology : JAT·Haoyu HuangDalin Hu
May 15, 2019·Cancers·Christian KaltschmidtBarbara Kaltschmidt
Jan 19, 2021·CNS Neuroscience & Therapeutics·Yu-Hua HuJian-Liang Wu
Feb 13, 2021·Molecular Therapy Oncolytics·Hans-Georg WirschingMichael Weller
Feb 26, 2021·Frontiers in Pharmacology·Lan-Ya LiYan Cheng
Aug 2, 2021·Cellular and Molecular Life Sciences : CMLS·Mariana MedeirosMaría Sol Brassesco

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