Abstract
Glioblastoma (GBM) is the most lethal primary brain cancer that lacks effective molecular targeted therapies. The PI3K/AKT/mTOR pathway is activated in 90% of all Glioblastoma multiforme (GBM) tumors. To gain insight into the impact of the PI3K pathway on GBM metabolism, we treated U87MG GBM cells with NVP-BEZ235 (PI3K and mTOR a dual inhibitor) and identified differentially expressed genes with RNA-seq analysis. RNA-seq identified 7803 differentially regulated genes in response to NVP-BEZ235. Gene Set Enrichment Analysis (GSEA) identified two glycolysis-related gene sets that were significantly enriched (p < 0.05) in control samples compared to NVP-BEZ235-treated samples. We validated the inhibition of glycolytic genes by NVP-BEZ235 and examined the impact of the FOXO1 inhibitor (AS1842856) on these genes in a set of GBM cell lines. FOXO1 inhibition alone was associated with reduced LDHA expression, but not ENO1 or PKM2. Bioinformatics analyses revealed that PI3K-impacted glycolytic genes were over-expressed and co-expressed in GBM clinical samples. The elevated expression of PI3K-impacted glycolytic genes was associated with poor prognosis in GBM based on Kaplan–Meier survival analyses. Our results suggest novel insights into hallmark metabolic reprogramming associated with the PI3K-mTOR dual inhibition.
Highlights
Cancer is the second leading cause of death in the United States
Genome mapping followed by comparative gene expression analysis between NVP-BEZ235-treated and control samples led to the identification of 7803 differentially expressed genes (DEGs)
We found that glycolysis-related genes were significantly downregulated by phosphatidylinositol 3-kinase (PI3K)-mTOR inhibition by NVP-BEZ235 in Glioblastoma multiforme (GBM) cells
Summary
Glioblastoma multiforme (GBM) is the most fatal, neurologically destructive, and common brain tumor of the central nervous system (CNS) [1]. GBM (grade IV glioma) is highly proliferative and classified as low-grade and high-grade glioblastoma (LGG and HGG) as per WHO standards [1,2]. GBM develops from astrocytes, oligodendrocytes, or from their precursors, and represents ~80% of the total malignant tumors of the CNS [1,2]. GBM is characterized by rapid growth, aggressive invasion, high rate of recurrence, neovascularization, and poor prognosis [2,3,4]. GBM is the highest occurring malignant brain tumor in the United States and has median survival period of ~15 months [2,5,6]
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