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

ABSTRACT: The peroxisome proliferator-activated receptor ? coactivator (PGC)-1? is a master regulator of mitochondrial biogenesis and controls metabolism by coordinating transcriptional events. Here, we interrogated whether PGC-1? is involved in tumor growth and the metabolic flexibility of glioblastoma cells. PGC-1? was expressed in a subset of established glioma cell lines and primary glioblastoma cell cultures. Furthermore, a higher PGC-1? expression was associated with an adverse outcome in the TCGA glioblastoma dataset. Suppression of PGC-1? expression by shRNA in the PGC-1?-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-1? functions in reactive oxygen species (ROS) metabolism, glioblastoma cells deficient in PGC-1? 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-1?sh cells also had impaired proliferation and migration rates in vitro and displayed less stem cell characteristics. Complementary effects were observed in PGC-1?-low LNT-229 cells engineered to overexpress PGC-1?. In an in vivo xenograft experiment, tumors formed by U343MG PGC-1?sh glioblastoma cells grew much slower than control tumors and were less invasive. Interestingly, the PGC-1? 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-1? modifies the neoplastic phenotype of glioblastoma cells toward more aggressive behavior and therefore makes PGC-1? a potential target for anti-glioblastoma therapies.

SUBMITTER: Bruns I 

PROVIDER: S-EPMC6398126 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature