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

Area of Science:

• Neuro-oncology
• Cancer Metabolism
• Molecular Biology

Background:

• Glioblastoma (GBM) is an aggressive brain cancer characterized by metabolic reprogramming.
• Glycolytic inhibition is a therapeutic strategy, but its efficacy in GBM, especially under hypoxia, is uncertain.
• Glucose-6-phosphatase (G6PC) is upregulated in GBM compared to normal brain tissue.

Purpose of the Study:

• To investigate the role of G6PC in GBM metabolic adaptation and malignant progression.
• To determine if G6PC counteracts glycolytic inhibition in GBM cells.
• To evaluate G6PC as a potential therapeutic target for GBM.

Main Methods:

• Analysis of G6PC expression in GBM and normal brain.
• Utilizing human-derived brain tumor-initiating cells (BTICs).
• Employing 2-deoxy-d-glucose (2DG) for glycolytic inhibition and G6PC knockdown experiments.
• Assessing cell migration, invasion, proliferation, and differentiation.

Main Results:

• GBM exhibits elevated G6PC expression.
• BTICs utilize G6PC to overcome 2DG-induced glycolytic inhibition and maintain proliferation.
• G6PC knockdown leads to cell death under glycolytic inhibition, glycogen accumulation, and reduced GBM aggressiveness (migration, invasion, proliferation).
• Surviving cells after G6PC knockdown show increased astrocytic differentiation.

Conclusions:

• G6PC is a key enzyme that promotes GBM malignancy by enabling metabolic adaptation.
• G6PC plays a critical role in counteracting glycolytic inhibition in GBM.
• G6PC represents a novel therapeutic target for GBM treatment.