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

28 Citations (Scopus)

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
Externally publishedYes

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Glucose-6-Phosphatase
Glioblastoma
Brain Neoplasms
Glycogen Phosphorylase
Glycogen Synthase
Tumor Microenvironment
Neoplastic Stem Cells
Deoxyglucose
Enzymes
Glycogen
Down-Regulation
Survival
Brain
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Glucose-6-phosphatase is a Key Metabolic Regulator of Glioblastoma Invasion. / Abbadi, Sara; Rodarte, Julio J.; Abutaleb, Ameer; Lavell, Emily; Smith, Chris L.; Ruff, William; Schiller, Jennifer; Olivi, Alessandro; Levchenko, Andre; Guerrero Cazares, Hugo; Quinones-Hinojosa, Alfredo.

In: Molecular Cancer Research, Vol. 12, No. 11, 01.11.2014, p. 1547-1559.

Research output: Contribution to journalArticle

Abbadi, S, Rodarte, JJ, Abutaleb, A, Lavell, E, Smith, CL, 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, vol. 12, no. 11, pp. 1547-1559. https://doi.org/10.1158/1541-7786.MCR-14-0106-T
Abbadi S, Rodarte JJ, Abutaleb A, Lavell E, Smith CL, Ruff W et al. Glucose-6-phosphatase is a Key Metabolic Regulator of Glioblastoma Invasion. Molecular Cancer Research. 2014 Nov 1;12(11):1547-1559. https://doi.org/10.1158/1541-7786.MCR-14-0106-T
Abbadi, Sara ; Rodarte, Julio J. ; Abutaleb, Ameer ; Lavell, Emily ; Smith, Chris L. ; Ruff, William ; Schiller, Jennifer ; Olivi, Alessandro ; Levchenko, Andre ; Guerrero Cazares, Hugo ; Quinones-Hinojosa, Alfredo. / Glucose-6-phosphatase is a Key Metabolic Regulator of Glioblastoma Invasion. In: Molecular Cancer Research. 2014 ; Vol. 12, No. 11. pp. 1547-1559.
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