PI3K Pathway Inhibition with NVP-BEZ235 Hinders Glycolytic Metabolism in Glioblastoma Multiforme Cells

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.

Advancing glioblastoma treatment by targeting metabolism

“…Shreya et al found that inhibiting PI3K-mTOR resulted in decreased levels of glycolytic metabolites, including a significant reduction in NAD+ and glutamate metabolites in GBM. Moreover, decreased glucose uptake and lactate secretion were also observed in this study [72] .…”

Forkhead box transcription factors (FOXOs and FOXM1) in glioma: from molecular mechanisms to therapeutics

“…In GBM cells, upon either FOXO1 or PI3K/mTOR inhibition, the expression of genes involved in glycolysis, such as LDHA, is reduced. However, surprisingly when both of them are inhibited, not only LDHA but ENO1 as glycolytic genes associated with poorer survival are increased, supporting the theory that for the efficacy of PI3/mTOR inhibitors against glycolysis, the intact activity of FOXO1 is necessary [ 143 ](Fig. 5 B).…”

“…In addition, PI3K/mTOR or FOXO1 inhibitors could prevent glycolysis in gliomas. However, when both of them are concurrently inhibited, the expression of glycolysis-related genes, including LDHA and ENO1, is elevated [ 143 ].…”

PI3K/mTOR inhibitors promote G6PD autophagic degradation and exacerbate oxidative stress damage to radiosensitize small cell lung cancer

“…EGFR signaling also induces the downstream activation of HIF-1 and PI3K/AKT/mTOR signaling, which rewires glycolysis and the PPP [ 47 ]. The PI3K/AKT/mTOR pathway not only increased glycolysis by elevating the expression of glucose transporters and the glycolytic rate but also decoupled glycolysis and the TCA cycle and diverted metabolic intermediates to the PPP branching metabolic pathway [ 48 , 49 ]. The increased flux in glycolysis and the PPP provided survival benefits to cancer cells after radiation.…”