Abstract
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.
Highlights
The peroxisome proliferator–activated receptor ␥ coactivator (PGC)-1␣ is a master regulator of mitochondrial biogenesis and controls metabolism by coordinating transcriptional events
Since we previously found that Akt/mTOR and AMPK have profound effects on the growth, metabolism, and resistance of glioblastoma cells against hypoxia [5, 6, 21] and these kinases converge on PGC-1␣, we here investigated the role of PGC-1␣ for metabolism and the neoplastic phenotype of glioblastomas
To gain insight into the function of PGC-1␣ in glioblastoma cells, the expression of PGC-1␣ was blocked by stable transfection with a short hairpin RNA (PGC-1␣sh) plasmid in U343MG cells, which endogenously strongly expresses PGC-1␣
Summary
The peroxisome proliferator–activated receptor ␥ coactivator (PGC)-1␣ is a master regulator of mitochondrial biogenesis and controls metabolism by coordinating transcriptional events. One of the most important mediators of metabolic adaptation is the transcriptional coactivator peroxisome proliferator-activated receptor ␥ coactivator (PGC)-1␣ It belongs to the PGC family and, in a tissue-specific manner, is responsive to different physiological stimuli like nutrient supply and oxygen concentration. According to the tissue where it is expressed, PGC-1␣ activity is induced by increased energy demand, such as cold temperature and exercise, or when energy yield needs to be optimized, during fasting [7, 12, 14] Another function of PGC-1␣ is the regulation of antioxidative responses and coordination of posttranscriptional events [15, 16]. Phosphorylacular endothelial growth factor; PI, propidium iodide; PPP, pentosephosphate-pathway; AMPK, AMP-activated protein kinase; NRF, nuclear respiratory family; SCRsh, scrambled shRNA sequence; bFGF-2, basic fibroblast growth factor-2; FFPE, formalin-fixed, paraffin-embedded; qPCR, quantitative PCR; PPAR, peroxisome proliferator-activated receptor. Since we previously found that Akt/mTOR and AMPK have profound effects on the growth, metabolism, and resistance of glioblastoma cells against hypoxia [5, 6, 21] and these kinases converge on PGC-1␣, we here investigated the role of PGC-1␣ for metabolism and the neoplastic phenotype of glioblastomas
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