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

Feb 27, 2018Journal of neurochemistry

Gene regulation of DNA repair and drug resistance in aggressive brain tumors

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Abstract

S cells exhibit higher levels of MGMT compared to M cells, which is associated with reduced sensitivity to temozolomide.

MGMT promoter methylation is a predictive biomarker for response to alkylating chemotherapy in glioblastoma.
Glioma-initiating cells (GIC) with stem-like features show increased MGMT expression compared to differentiated cells.
Transitioning GIC from sphere to adherent cultures leads to decreased MGMT expression and heightened sensitivity to temozolomide.
Increased expression of the NF-κB pathway components p50/p65 is observed in S cells, correlating with MGMT overexpression.
Inhibition of NF-κB reduces MGMT levels, suggesting a role in alkylator resistance in this glioma stem-like cell model.

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O-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, BAY 11-7082, or siRNA-mediated gene silencing, reduced MGMT levels. In summary, alkylator resistance of S cells is mainly promoted by over-expression of MGMT which results from increased activity of the NF-κB pathway in this cell culture model of glioma stem-like cells. Read the Editorial Highlight for this article on page 688. 6

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

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