TY - JOUR
T1 - Glucose-6-phosphatase is a Key Metabolic Regulator of Glioblastoma Invasion
AU - Abbadi, Sara
AU - Rodarte, Julio J.
AU - Abutaleb, Ameer
AU - Lavell, Emily
AU - Smith, Chris L.
AU - Ruff, William
AU - Schiller, Jennifer
AU - Olivi, Alessandro
AU - Levchenko, Andre
AU - Guerrero-Cazares, Hugo
AU - Quinones-Hinojosa, Alfredo
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-14-0106-T
DO - 10.1158/1541-7786.MCR-14-0106-T
M3 - Article
C2 - 25001192
AN - SCOPUS:84910668346
SN - 1541-7786
VL - 12
SP - 1547
EP - 1559
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 11
ER -