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Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell
Roy Blum1, Jasmine Jacob-Hirsch, Ninette Amariglio
1Department of Neurobiochemistry, George S. Wise Faculty of Life Sciences and Sackler School of Medicine, Tel-Aviv University, 66978 Tel-Aviv, Israel.
Abstract:
Active Ras and phosphatidylinositol-3-kinase-dependent pathways contribute to the malignant phenotype of glioblastoma multiformes (GBM). Here we show that the Ras inhibitor trans-farnesylthiosalicylic acid (FTS) exhibits profound antioncogenic effects in U87 GBM cells. FTS inhibited active Ras and attenuated Ras signaling to extracellular signal-regulated kinase, phosphatidylinositol-3-kinase, and Akt. Concomitantly, hypoxia-inducible factor 1alpha (HIF-1alpha) disappeared, expression of key glycolysis pathway enzymes and of other HIF-1alpha-regulated genes (including vascular endothelial growth factor and the Glut-1 glucose transporter) was down-regulated, and glycolysis was halted. This led to a dramatic reduction in ATP, resulting in a severe energy crisis. In addition, the expression of E2F-regulated genes was down-regulated in the FTS-treated cells. Consequently, U87 cell growth was arrested and the cells died. These results show that FTS is a potent down-regulator of HIF-1alpha and might therefore block invasiveness, survival, and angiogenesis in GBM.
Insights
Trans-farnesylthiosalicylic acid (FTS), a Ras inhibitor, halts glioblastoma multiforme (GBM) cell growth by blocking energy production and down-regulating key survival pathways. FTS demonstrates significant antioncogenic effects against GBM.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Glioblastoma multiforme (GBM) exhibits a malignant phenotype driven by active Ras and phosphatidylinositol-3-kinase (PI3K) pathways.
- Targeting these signaling pathways presents a therapeutic strategy for GBM treatment.
Purpose of the Study:
- To investigate the antioncogenic effects of the Ras inhibitor trans-farnesylthiosalicylic acid (FTS) in U87 GBM cells.
- To elucidate the molecular mechanisms underlying FTS's effects on GBM cell signaling, metabolism, and proliferation.
Main Methods:
- Treatment of U87 GBM cells with trans-farnesylthiosalicylic acid (FTS).
- Analysis of Ras signaling, including extracellular signal-regulated kinase (ERK) and Akt.
- Assessment of hypoxia-inducible factor 1-alpha (HIF-1alpha) expression and its downstream targets.
- Measurement of glycolysis, ATP levels, and cell growth.
Main Results:
- FTS inhibited active Ras and attenuated downstream signaling pathways (ERK, PI3K, Akt).
- FTS treatment led to the disappearance of HIF-1alpha, down-regulation of HIF-1alpha-regulated genes (e.g., VEGF, Glut-1), and halted glycolysis.
- This resulted in reduced ATP levels, energy crisis, down-regulation of E2F-regulated genes, cell growth arrest, and cell death.
Conclusions:
- FTS exhibits potent antioncogenic effects in GBM cells by inhibiting Ras signaling and down-regulating HIF-1alpha.
- FTS effectively blocks GBM cell invasiveness, survival, and angiogenesis by disrupting energy metabolism and cell cycle progression.
