title: Glucose-6-phosphatase is a key metabolic regulator of glioblastoma invasion.
abstract: Glioblastoma (GBM) remains the most aggressive primary brain cancer in adults. Similar to other cancers, GBM cells undergo metabolic reprogramming to promote proliferation and survival. Glycolytic inhibition is widely used to target such reprogramming. However, the stability of glycolytic inhibition in GBM remains unclear especially in a hypoxic tumor microenvironment. In this study, it was determined that glucose-6-phosphatase (G6PC/G6Pase) expression is elevated in GBM when compared with normal brain. Human-derived brain tumor-initiating cells (BTIC) use this enzyme to counteract glycolytic inhibition induced by 2-deoxy-d-glucose (2DG) and sustain malignant progression. Downregulation of G6PC renders the majority of these cells unable to survive glycolytic inhibition, and promotes glycogen accumulation through the activation of glycogen synthase (GYS1) and inhibition of glycogen phosphorylase (PYGL). Moreover, BTICs that survive G6PC knockdown are less aggressive (reduced migration, invasion, proliferation, and increased astrocytic differentiation). Collectively, these findings establish G6PC as a key enzyme with promalignant functional consequences that has not been previously reported in GBM and identify it as a potential therapeutic target.
  
  
  CONCLUSIONS
  This study is the first to demonstrate a functional relationship between the critical gluconeogenic and glycogenolytic enzyme G6PC with the metabolic adaptations during GBM invasion.
authors.affiliation: Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Sara
authors.initials: S
authors.lastname: Abbadi
authors.affiliation: Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Julio J
authors.initials: JJ
authors.lastname: Rodarte
authors.affiliation: University of Maryland, School of Medicine, Baltimore, Maryland.
authors.forename: Ameer
authors.initials: A
authors.lastname: Abutaleb
authors.affiliation: Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Emily
authors.initials: E
authors.lastname: Lavell
authors.affiliation: Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Chris L
authors.initials: CL
authors.lastname: Smith
authors.affiliation: Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: William
authors.initials: W
authors.lastname: Ruff
authors.affiliation: Brandeis University, Waltham, Massachusetts.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schiller
authors.affiliation: Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Olivi
authors.affiliation: Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Andre
authors.initials: A
authors.lastname: Levchenko
authors.affiliation: Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. aquinon2@jhmi.edu hguerre1@jhmi.edu.
authors.forename: Hugo
authors.initials: H
authors.lastname: Guerrero-Cazares
authors.affiliation: Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. aquinon2@jhmi.edu hguerre1@jhmi.edu.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Quinones-Hinojosa
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001932:Brain Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D005952:Glucose-6-Phosphatase / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D024981:Glycogen Phosphorylase / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D034741:RNA, Small Interfering; D006003:Glycogen; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; D005952:Glucose-6-Phosphatase