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-α (G6PC/G6Pase) expression is elevated in GBM when compared to normal brain. Human-derived brain tumor initiating cells (BTICs) utilize this enzyme to counteract glycolytic inhibition induced by 2-Deoxy-D-glucose (2DG) and sustain malignant progression. Down-regulation 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 pro-malignant functional consequences that has not been previously reported in GBM and identify it as a potential therapeutic target.

Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization

“…PTEN L320S -GFP, PTEN T277A -GFP, and PTEN delEx3 -GFP showed decreased activity to suppress cell migration, as measured by the Transwell (Fig. 1K) or 3-D nanopattern migration assays 2, 41, 42 (Fig. 1L).…”

Genetic and molecular analyses reveal G6PC as a key element connecting glucose metabolism and cell cycle control in ovarian cancer

“…We therefore investigated the role of G6PC, a key enzyme in gluconeogenesis and glycogenolysis in OvCa [10]. We investigated a panel of glucose metabolism genes using TCGAOvCa dataset and found that G6PC was overexpressed in 17 % of cases, a frequency higher than that for most other genes related to glucose metabolism (Fig.…”

“…One of the key enzymes that regulate glucose homeostasis and glycogenolysis is glucose-6-phosphatase, catalytic subunit (G6PC), which is located at the membrane of the endoplasmic reticulum [9]. Due to its physiologically important role in glycogenolysis and its critical tumourigenic role in glioblastoma [10], we hypothesize that G6PC plays critical roles in OvCa and that targeting it will commit OvCa to cell death.…”

Cerebral Gluconeogenesis and Diseases

“…It has been observed that cancer stem cells from glioblastomas depend on G6PC and use the enzyme to counteract glycolytic inhibition (Abbadi et al, 2014). Interestingly, the knockdown of G6PC was able to decrease the aggressive phenotype of glioblastoma stem cells, potentially through the downregulation of the CD133/AKT pathway and an increase in glycogen accumulation through activation of GS and inhibition of glycogen phosphorylase, which has been previously shown to induce cancer cell death (Lee et al, 2004; Favaro et al, 2012).…”

“…Interestingly, the knockdown of G6PC was able to decrease the aggressive phenotype of glioblastoma stem cells, potentially through the downregulation of the CD133/AKT pathway and an increase in glycogen accumulation through activation of GS and inhibition of glycogen phosphorylase, which has been previously shown to induce cancer cell death (Lee et al, 2004; Favaro et al, 2012). G6PC knockdown also reduced migration, invasion, and cell viability (Abbadi et al, 2014). A number of studies have suggested that cancer cells have elevated levels of glycogen (Rousset et al, 1981), which is accumulated in response to hypoxic stimulation for later use in several cancer cell lines (Pelletier et al, 2012).…”