Disruption of peroxisome proliferator–activated receptor γ coactivator (PGC)-1α reverts key features of the neoplastic phenotype of glioma cells

Bruns, Ines; Sauer, Benedikt; Burger, Michael C.; Eriksson, Jule A.; Hofmann, Ute; Braun, Yannick; Harter, Patrick N.; Luger, Anna‐Luisa; Ronellenfitsch, Michael; Steinbach, Joachim P.; Rieger, Johannes

doi:10.1074/jbc.ra118.006993

Cited by 25 publications

(23 citation statements)

References 57 publications

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“…2 e). This concept that a higher oxygen consumption correlates with enhanced sensitivity to hypoxia-induced cell death has previously been reported for PPARGC1A (PGC-1α) overexpressing GB cells 31 . In contrast, pharmacological ATF4 induction with tunicamycin resulted in a reduced oxygen consumption compared to vehicle treated LNT-229 and G55 cells (Fig.…”

Section: Discussionsupporting

confidence: 74%

Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide

Lorenz

Sittig

Urban

et al. 2021

Sci Rep

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The integrated stress response (ISR) is a central cellular adaptive program that is activated by diverse stressors including ER stress, hypoxia and nutrient deprivation to orchestrate responses via activating transcription factor 4 (ATF4). We hypothesized that ATF4 is essential for the adaptation of human glioblastoma (GB) cells to the conditions of the tumor microenvironment and is contributing to therapy resistance against chemotherapy. ATF4 induction in GB cells was modulated pharmacologically and genetically and investigated in the context of temozolomide treatment as well as glucose and oxygen deprivation. The relevance of the ISR was analyzed by cell death and metabolic measurements under conditions to approximate aspects of the GB microenvironment. ATF4 protein levels were induced by temozolomide treatment. In line, ATF4 gene suppressed GB cells (ATF4sh) displayed increased cell death and decreased survival after temozolomide treatment. Similar results were observed after treatment with the ISR inhibitor ISRIB. ATF4sh and ISRIB treated GB cells were sensitized to hypoxia-induced cell death. Our experimental study provides evidence for an important role of ATF4 for the adaptation of human GB cells to conditions of the tumor microenvironment characterized by low oxygen and nutrient availability and for the development of temozolomide resistance. Inhibiting the ISR in GB cells could therefore be a promising therapeutic approach.

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Section: Discussionsupporting

confidence: 74%

Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide

Lorenz

Sittig

Urban

et al. 2021

Sci Rep

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“…Notably, PGC1 α can regulate the expression of various antioxidant genes and play an important regulatory role in redox homeostasis [ 41 ]. Bruns et al reported that PGC1 α plays an important role in the clearance of ROS by regulating SOD1 and SOD2 in GBM glioblastoma cells [ 42 ]. In addition, a study using an aging disease model found that PGC1 α can regulate Nrf2 expression and play a synergistic role in antioxidation [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

The Nrf2/PGC1α Pathway Regulates Antioxidant and Proteasomal Activity to Alter Cisplatin Sensitivity in Ovarian Cancer

Deng

Lin

et al. 2020

Oxidative Medicine and Cellular Longevity

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Drug resistance remains a barrier in the clinical treatment of ovarian cancer. Proteasomal and antioxidant activities play important roles in tumor drug resistance, and increasing evidence suggests the existence of an interaction between antioxidant and proteasomal activities. However, the mechanism of the synergistic effects of proteasomal activity and antioxidation on tumor drug resistance is not completely clear. In this study, we compared two ovarian cancer cells, A2780 and SKOV3 cells. Among them, SKOV3 cell is a human clear cell carcinoma cell line that is resistant to platinum. We found that compared with the findings in A2780 cells, SKOV3 cells were less sensitive to both proteasomal inhibitor and cisplatin. Proteasomal inhibition enhanced the sensitivity of A2780 cells, but not SKOV3 cells, to cisplatin. Notably, the Nrf2-mediated antioxidant pathway was identified as a resistance mechanism in proteasome inhibitor-resistant cells, but this was not the only factor identified in our research. In SKOV3 cells, PGC1α regulated the antioxidant activity of Nrf2 by increasing the phosphorylation of GSK3β, and in turn, Nrf2 regulated the transcriptional activity of PGC1α. Thus, Nrf2 and PGC1α synergistically participate in the regulation of proteasomal activity. Furthermore, the Nrf2/PGC1α pathway participated in the regulation of mitochondrial function and homeostasis, further regulating proteasomal activity in SKOV3 cells. Therefore, exploring the roles of PGC1α and Nrf2 in the regulation of proteasomal activity by antioxidant and mitochondrial functions may provide new avenues for reversing drug resistance in ovarian cancer.

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“…Sirtuin 1 (SIRT1) is involved in the redox balance and carcinogenesis, including the proliferation of GBM cells [ 61 ]. Peroxisome proliferator-activated receptor γ coactivator1α (PGC-1α) regulates energy metabolism and oxidative stress, evoking a more aggressive behaviour of GBM cells [ 62 ]. Nuclear erythroid factor 2-related factor 2 (NRF2) is a redox-sensitive transcription factor regulating the expression of antioxidant enzymes such as SOD [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Glutaminase isoforms expression switches microRNA levels and oxidative status in glioblastoma cells

et al. 2021

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Background Glutaminase isoenzymes GLS and GLS2 play apparently opposing roles in cancer: GLS acts as an oncoprotein, while GLS2 (GAB isoform) has context specific tumour suppressive activity. Some microRNAs (miRNAs) have been implicated in progression of tumours, including gliomas. The aim was to investigate the effect of GLS and GAB expression on both miRNAs and oxidative status in glioblastoma cells. Methods Microarray profiling of miRNA was performed in GLS-silenced LN229 and GAB-transfected T98G human glioblastoma cells and their wild-type counterparts. Results were validated by real-time quantitative RT-PCR. Oxidative status and antioxidant enzymes were determined by spectrophotometric or fluorescence assays in GLS-silenced LN229 and T98G, and GAB-transfected LN229 and T98G. Results MiRNA-146a-5p, miRNA-140-3p, miRNA-21-5p, miRNA-1260a, and miRNA-92a-3p were downregulated, and miRNA-1246 was upregulated when GLS was knocked down. MiRNA-140-3p, miRNA-1246, miRNA-1260a, miRNA-21-5p, and miRNA-146a-5p were upregulated when GAB was overexpressed. Oxidative status (lipid peroxidation, protein carbonylation, total antioxidant capacity, and glutathione levels), as well as antioxidant enzymes (catalase, superoxide dismutase, and glutathione reductase) of silenced GLS glioblastoma cells and overexpressed GAB glioblastoma cells significantly changed versus their respective control glioblastoma cells. MiRNA-1246, miRNA-1260a, miRNA-146a-5p, and miRNA-21-5p have been characterized as strong biomarkers of glioblastoma proliferation linked to both GLS silencing and GAB overexpression. Total glutathione is a reliable biomarker of glioblastoma oxidative status steadily associated to both GLS silencing and GAB overexpression. Conclusions Glutaminase isoenzymes are related to the expression of some miRNAs and may contribute to either tumour progression or suppression through certain miRNA-mediated pathways, proving to be a key tool to switch cancer proliferation and redox status leading to a less malignant phenotype. Accordingly, GLS and GAB expression are especially involved in glutathione-dependent antioxidant defence.

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Disruption of peroxisome proliferator–activated receptor γ coactivator (PGC)-1α reverts key features of the neoplastic phenotype of glioma cells

Cited by 25 publications

References 57 publications

Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide

Activating transcription factor 4 mediates adaptation of human glioblastoma cells to hypoxia and temozolomide

The Nrf2/PGC1α Pathway Regulates Antioxidant and Proteasomal Activity to Alter Cisplatin Sensitivity in Ovarian Cancer

Glutaminase isoforms expression switches microRNA levels and oxidative status in glioblastoma cells

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