Glucose-6-phosphatase is a Key Metabolic Regulator of Glioblastoma Invasion

Sara Abbadi, Julio J. Rodarte, Ameer Abutaleb, Emily Lavell, Chris L. Smith, William Ruff, Jennifer Schiller, Alessandro Olivi, Andre Levchenko, Hugo Guerrero-Cazares, Alfredo Quinones-Hinojosa

Research output: Contribution to journalArticle

32 Scopus citations

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 inGBMremains 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.

Original languageEnglish (US)
Pages (from-to)1547-1559
Number of pages13
JournalMolecular Cancer Research
Volume12
Issue number11
DOIs
StatePublished - Nov 1 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Abbadi, S., Rodarte, J. J., Abutaleb, A., Lavell, E., Smith, C. L., Ruff, W., Schiller, J., Olivi, A., Levchenko, A., Guerrero-Cazares, H., & Quinones-Hinojosa, A. (2014). Glucose-6-phosphatase is a Key Metabolic Regulator of Glioblastoma Invasion. Molecular Cancer Research, 12(11), 1547-1559. https://doi.org/10.1158/1541-7786.MCR-14-0106-T