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

• Published in: The Journal of biological chemistry 2019-03, Vol.294 (9), p.3037-3050
• Main Authors: Bruns, Ines, Sauer, Benedikt, Burger, Michael C., Eriksson, Jule, Hofmann, Ute, Braun, Yannick, Harter, Patrick N., Luger, Anna-Luisa, Ronellenfitsch, Michael W., Steinbach, Joachim P., Rieger, Johannes
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Energy Metabolism - genetics; ErbB Receptors - metabolism; Gene Expression Regulation, Neoplastic - genetics; Gene Knockdown Techniques; glioblastoma; Glioblastoma - pathology; Glucose - metabolism; Homeostasis - genetics; Humans; hypoxia; Mitochondria - genetics; Molecular Bases of Disease; Neoplastic Stem Cells - pathology; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - deficiency; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) (PPARGC1A); Phenotype; reactive oxygen species (ROS); Reactive Oxygen Species - metabolism; Signal Transduction - genetics; transcription coactivator; Tumor Hypoxia - genetics; tumor metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.006993

The peroxisome proliferator–activated receptor γ coactivator (PGC)-1α is a master regulator of mitochondrial biogenesis and controls metabolism by coordinating transcriptional events. Here, we interrogated whether PGC-1α is involved in tumor growth and the metabolic flexibility of glioblastoma cells. PGC-1α was expressed in a subset of established glioma cell lines and primary glioblastoma cell cultures. Furthermore, a higher PGC-1α expression was associated with an adverse outcome in the TCGA glioblastoma dataset. Suppression of PGC-1α expression by shRNA in the PGC-1α–positive U343MG glioblastoma line suppressed mitochondrial gene expression, reduced mitochondrial membrane potential, and diminished oxygen as well as glucose consumption, and lactate production. Compatible with the known PGC-1α functions in reactive oxygen species (ROS) metabolism, glioblastoma cells deficient in PGC-1α displayed ROS accumulation, had reduced RNA levels of proteins involved in ROS detoxification, and were more susceptible to death induction by H2O2 compared with control cells. PGC-1αsh cells also had impaired proliferation and migration rates in vitro and displayed less stem cell characteristics. Complementary effects were observed in PGC-1α–low LNT-229 cells engineered to overexpress PGC-1α. In an in vivo xenograft experiment, tumors formed by U343MG PGC-1αsh glioblastoma cells grew much slower than control tumors and were less invasive. Interestingly, the PGC-1α knockdown conferred protection against hypoxia-induced cell death, probably as a result of less active anabolic pathways, and this effect was associated with reduced epidermal growth factor expression and mammalian target of rapamycin signaling. In summary, PGC-1α modifies the neoplastic phenotype of glioblastoma cells toward more aggressive behavior and therefore makes PGC-1α a potential target for anti-glioblastoma therapies.