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Therapeutic Drug-Induced Metabolic Reprogramming in Glioblastoma
Trang T T Nguyen1, Enyuan Shang2, Mike-Andrew Westhoff3
1Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
Abstract:
Glioblastoma WHO IV (GBM), the most common primary brain tumor in adults, is a heterogenous malignancy that displays a reprogrammed metabolism with various fuel sources at its disposal. Tumor cells primarily appear to consume glucose to entertain their anabolic and catabolic metabolism. While less effective for energy production, aerobic glycolysis (Warburg effect) is an effective means to drive biosynthesis of critical molecules required for relentless growth and resistance to cell death. Targeting the Warburg effect may be an effective venue for cancer treatment. However, past and recent evidence highlight that this approach may be limited in scope because GBM cells possess metabolic plasticity that allows them to harness other substrates, which include but are not limited to, fatty acids, amino acids, lactate, and acetate. Here, we review recent key findings in the literature that highlight that GBM cells substantially reprogram their metabolism upon therapy. These studies suggest that blocking glycolysis will yield a concomitant reactivation of oxidative energy pathways and most dominantly beta-oxidation of fatty acids.
Insights
Glioblastoma cells adapt their metabolism to survive treatment. Targeting glucose metabolism alone is insufficient, as these brain tumor cells can switch to utilizing fatty acids and other fuels.
Area of Science:
- Neuro-oncology
- Cancer Metabolism
- Molecular Biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with reprogrammed cellular metabolism.
- Aerobic glycolysis (Warburg effect) supports GBM growth and survival.
- Targeting the Warburg effect is a potential cancer therapy strategy.
Purpose of the Study:
- To review recent findings on metabolic reprogramming in GBM.
- To highlight GBM's metabolic plasticity and substrate utilization.
- To discuss therapeutic implications of metabolic adaptation.
Main Methods:
- Literature review of recent key findings.
- Analysis of metabolic pathways in GBM cells.
- Examination of metabolic shifts in response to therapy.
Main Results:
- GBM cells exhibit significant metabolic plasticity, utilizing diverse fuel sources beyond glucose.
- Therapy can induce metabolic reprogramming in GBM cells.
- Inhibition of glycolysis leads to the activation of alternative energy pathways, notably fatty acid beta-oxidation.
Conclusions:
- Targeting glycolysis alone may be ineffective against GBM due to metabolic adaptability.
- GBM's metabolic plasticity necessitates broader therapeutic strategies.
- Understanding and targeting alternative fuel sources are crucial for effective GBM treatment.
