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Mol Cancer Res. 2014 Nov;12(11):1547-59. doi: 10.1158/1541-7786.MCR-14-0106-T. Epub 2014 Jul 7.

Glucose-6-phosphatase is a key metabolic regulator of glioblastoma invasion.

Author information

1
Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
University of Maryland, School of Medicine, Baltimore, Maryland.
3
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.
4
Brandeis University, Waltham, Massachusetts.
5
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.
6
Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland. aquinon2@jhmi.edu hguerre1@jhmi.edu.

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.

IMPLICATIONS:

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.

PMID:
25001192
PMCID:
PMC4233174
DOI:
10.1158/1541-7786.MCR-14-0106-T
[Indexed for MEDLINE]
Free PMC Article
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