Mitochondrial DNA Alterations in Glioblastoma (GBM)

Barros, Mariceli Baia Leão; Pinheiro, Danilo do Rosário; Borges, Bárbara do Nascimento

doi:10.3390/ijms22115855

Cited by 16 publications

(12 citation statements)

References 75 publications

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“…On the contrary, TMZ treatment was shown to stimulate mitochondrial respiration. Since the measurement of oxygen consumption was normalized to the number of viable cells, this activity could be attributed to its ability to increase the number of mitochondria per cell 45,46 . Nevertheless, the combination treatment in U87 GBM cells seems to make mitochondria more active.…”

Section: Discussionmentioning

confidence: 99%

“…Since the measurement of oxygen consumption was normalized to the number of viable cells, this activity could be attributed to its ability to increase the number of mitochondria per cell. 45 , 46 Nevertheless, the combination treatment in U87 GBM cells seems to make mitochondria more active. Bearing in mind that U87 cells rely primarily on glycolysis rather than OxPhos, 47 we could speculate that TMZ in the presence of DIA induced a shift in metabolic phenotype.…”

Section: Discussionmentioning

confidence: 99%

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Diazepam diminishes temozolomide efficacy in the treatment of U87 glioblastoma cell line

et al. 2022

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Aims: Many patients with glioblastoma (GBM) suffer from comorbid neurological/ psychiatric disorders and, therefore, are treated with psychopharmacological agents. Diazepam (DIA) is widely adopted to treat status epilepticus, alleviate anxiety, and inhibit chemotherapy-associated delayed emesis in GBM patients. Even though temozolomide (TMZ) and DIA could be found as possible combination therapy in clinical practice, there are no reports of their combined effects in GBM. Hence, it may be of interest to investigate whether DIA enhances the antitumor efficacy of TMZ in GBM cells.Methods: U87 human GBM was used to examine the effects of combined TMZ and DIA on cell viability, and the oxygen consumption within the cells, in order to evaluate mitochondrial bioenergetic response upon the treatment. Results:The cooperative index showed the presence of antagonism between TMZ and DIA, which was confirmed on long-term observation. Moreover, the level of apoptosis after the TMZ treatment was significantly decreased when administered with DIA (p < 0.001). Concomitant use of TMZ and DIA increased the basal cell respiration rate, the oxidative phosphorylation rate, and maximal capacity of mitochondrial

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Diazepam diminishes temozolomide efficacy in the treatment of U87 glioblastoma cell line

et al. 2022

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“…Indeed, some GSCs contain higher levels of ATP than differentiated GBM cells, complicating the overall picture of metabolic reprogramming and illustrating intratumoral heterogeneity at the metabolic level, while suggesting that purely targeting the glycolytic pathway may not be effective against all GSCs [ 66 , 67 ]. In fact, mutations are found throughout the mitochondrial DNA genome in GBM cells, altering metabolic pathways and energy generation and contributing to therapeutic resistance [ 68 ]. Certain GSC subtypes rely on the glycolytic pathway to greater extents than other subtypes, which also utilize the mitochondrial pathways, illustrating the need for multiple therapeutic targets [ 63 , 67 ].…”

Section: Interactions With Tumor Microenvironmentmentioning

confidence: 99%

Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

Hersh

Gaitsch

Alomari

et al. 2022

Cancers

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Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.

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“…An increasing number of studies have demonstrated that mitochondria play an important role in gliomas, including GBM. Mitochondrial DNA (mtDNA) alterations are associated with cellular and metabolic consequences, diagnosis, prognosis, and treatment of GBM [11]. Mitochondrial dynamics are reportedly essential for the development of gliomas.…”

Section: Introductionmentioning

confidence: 99%

Identification of SSBP1 as a ferroptosis-related biomarker of glioblastoma based on a novel mitochondria-related gene risk model and in vitro experiments

Liu

et al. 2022

J Transl Med

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Background Glioblastoma (GBM) is the most common primary malignant brain tumor that leads to lethality. Several studies have demonstrated that mitochondria play an important role in GBM and that mitochondria-related genes (MRGs) are potential therapeutic targets. However, the role of MRGs in GBM remains unclear. Methods Differential expression and univariate Cox regression analyses were combined to screen for prognostic differentially-expressed (DE)-MRGs in GBM. Based on LASSO Cox analysis, 12 DE-MRGs were selected to construct a risk score model. Survival, time dependent ROC, and stratified analyses were performed to evaluate the performance of this risk model. Mutation and functional enrichment analyses were performed to determine the potential mechanism of the risk score. Immune cell infiltration analysis was used to determine the association between the risk score and immune cell infiltration levels. CCK-8 and transwell assays were performed to evaluate cell proliferation and migration, respectively. Mitochondrial reactive oxygen species (ROS) levels and morphology were measured using a confocal laser scanning microscope. Genes and proteins expression levels were investigated by quantitative PCR and western blotting, respectively. Results We identified 21 prognostic DE-MRGs, of which 12 DE-MRGs were selected to construct a prognostic risk score model for GBM. This model presented excellent performance in predicting the prognosis of patients with GBM and acted as an independent predictive factor. Functional enrichment analysis revealed that the risk score was enriched in the inflammatory response, extracellular matrix, and pro-cancer-related and immune related pathways. Additionally, the risk score was significantly associated with gene mutations and immune cell infiltration in GBM. Single-stranded DNA-binding protein 1 (SSBP1) was considerably upregulated in GBM and associated with poor prognosis. Furthermore, SSBP1 knockdown inhibited GBM cell progression and migration. Mechanistically, SSBP1 knockdown resulted in mitochondrial dysfunction and increased ROS levels, which, in turn, increased temozolomide (TMZ) sensitivity in GBM cells by enhancing ferroptosis. Conclusion Our 12 DE-MRGs-based prognostic model can predict the GBM patients prognosis and 12 MRGs are potential targets for the treatment of GBM. SSBP1 was significantly upregulated in GBM and protected U87 cells from TMZ-induced ferroptosis, which could serve as a prognostic and therapeutic target/biomarker for GBM.

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Mitochondrial DNA Alterations in Glioblastoma (GBM)

Cited by 16 publications

References 75 publications

Diazepam diminishes temozolomide efficacy in the treatment of U87 glioblastoma cell line

Diazepam diminishes temozolomide efficacy in the treatment of U87 glioblastoma cell line

Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

Identification of SSBP1 as a ferroptosis-related biomarker of glioblastoma based on a novel mitochondria-related gene risk model and in vitro experiments

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