MGMT overexpression

In our cohort, MGMT expression seems helpful as a biomarker of good prognosis (low-grade and absence of muscle invasion). A heterogeneous methylation pattern in the MGMT gene requires additional investigation to elucidate its potential implications.

The regulation of MGMT ubiquitination by USP19 plays a critical role in DNA methylation damage repair and GBM patients' temozolomide chemotherapy response.

It was further determined that chronic low dose of Cr(VI) exposure-transformed BEAS-2B cells display impaired DNA damage repair capacity and a high sensitivity to the toxicity of the alkylating chemotherapeutic drug Temozolomide...Further mechanistical studies revealed that chronic low dose of Cr(VI) exposure down-regulates MGMT expression through epigenetic mechanisms by increasing DNA methylation and histone H3 repressive modifications. Taken together, these findings suggest that epigenetic down-regulation of a crucial DNA damage repair protein MGMT contributes significantly to the genotoxic effect and cell transformation caused by chronic low dose of Cr(VI) exposure.

Overall, our newly developed isogenic rat and mouse glioma models recapitulate MGMT-dependent TMZ sensitivity and provide useful preclinical tools for studying MGMT as a biomarker and potential therapeutic target in GBM. In addition, these syngeneic models facilitate studies on the immune modulation of chemotherapeutic agents in the context of MGMT expression and allows for testing of chemoimmunotherapy combinations.

Our study provides the first evidence that quercetin may induce apoptosis in MGMTGBM cells via dual inhibition of the Wnt3a/β-Catenin pathway and the Akt/NF-κB signaling pathway. These findings suggest that quercetin could be a novel agent for improving GBM treatment, especially in TMZ-resistant GBM with high MGMT expression.

Down-regulation of Wnt antagonist secreted frizzled-related protein 4 (sFRP4) in GBM and GSCs, indicating activation of the Wnt/β-catenin pathway, which could be involved in the conversion of iPSCs to CSCs. From future perspectives, our study will help in the creation of a rapid cell-based platform for understanding the complexity of GBM.

Reactive oxygen species-mediated DNA damage is at least partially involved. Combinational administration of NCT503 and TMZ may represent a novel and promising treatment strategy to enhance TMZ efficacy in patients with MGMT-high glioblastoma.

COL6A2 high-expression is an indicator for adverse glioma prognosis, and is correlated with TMZ-resistant and immune response. Meanwhile, it may be a prospective biomarker for treatment.

Those mechanisms must be evaluated to get a better understanding of the origin of the resistance. These data may support the development of new treatment strategies.

Mannose inhibited MGMT to enhance sensitivity of glioma cells to TMZ, with Wnt/β-catenin pathway involvement. Our data suggested that mannose could be an innovative agent to improve glioma treatment, particularly in TMZ-resistant glioma with high MGMT.