Abstract
BackgroundIntratumor subsets with tumor-initiating features in glioblastoma are likely to survive treatment. Our goal is to identify the key factor in the process by which cells develop temozolomide (TMZ) resistance.MethodsResistant cell lines derived from U87MG and A172 were established through long-term co-incubation of TMZ. Primary tumors obtained from patients were maintained as patient-derived xenograft for studies of tumor-initating cell (TIC) features. The cell manifestations were assessed in the gene modulated cells for relevance to drug resistance.ResultsAmong the mitochondria-related genes in the gene expression databases, superoxide dismutase 2 (SOD2) was a significant factor in resistance and patient survival. SOD2 in the resistant cells functionally determined the cell fate by limiting TMZ-stimulated superoxide reaction and cleavage of caspase-3. Genetic inhibition of the protein led to retrieval of drug effect in mouse study. SOD2 was also associated with the TIC features, which enriched in the resistant cells. The CD133+ specific subsets in the resistant cells exhibited superior superoxide regulation and the SOD2-related caspase-3 reaction. Experiments applying SOD2 modulation showed a positive correlation between the TIC features and the protein expression. Finally, co-treatment with TMZ and the SOD inhibitor sodium diethyldithiocarbamate trihydrate in xenograft mouse models with the TMZ-resistant primary tumor resulted in lower tumor proliferation, longer survival, and less CD133, Bmi-1, and SOD2 expression.ConclusionSOD2 plays crucial roles in the tumor-initiating features that are related to TMZ resistance. Inhibition of the protein is a potential therapeutic strategy that can be used to enhance the effects of chemotherapy.Graphical abstract
Highlights
Intratumor subsets with tumor-initiating features in glioblastoma are likely to survive treatment
superoxide dismutase 2 (SOD2) expression was associated with TMZ resistance in GBM To explore the critical factors in treatment resistance, cell models of acquired resistance were derived from U87MG and A172 cells (U87MG-r#10 and A172-r#6, respectively) [14]
Cells were treated for 3 days and cultured until Day 7 (*P < 0.05). c Flowchart of differentiating the mitochondria-related genes that significantly differed in TMZ-resistant cells
Summary
Intratumor subsets with tumor-initiating features in glioblastoma are likely to survive treatment. Our goal is to identify the key factor in the process by which cells develop temozolomide (TMZ) resistance. Glioblastoma (GBM) is a fatal disease with a mean survival of approximately only one year, even with comprehensive treatment [1]. Pre-existing O6-methylguanine-DNA methyltransferase (MGMT) is the only known single contributory gene that has been clearly described [5]. This gene is associated more with innate resistance, and together with other DNA repair genes, might serve as a predictor of drug response [6]. Much uncertainty exists in regard to the ability of cells to acquire resistance due to the complicated and multifactorial mechanisms involved in TMZ resistance
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