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Updated: May 31, 2026
Therapy Testing in a Spheroid-based 3D Cell Culture Model for Head and Neck Squamous Cell Carcinoma
Published on: April 20, 2018
Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational
Vlad C Sandulache1, Heath D Skinner, Thomas J Ow
1Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, USA.
Background:
Mutations in the tumor protein 53 (TP53) tumor suppressor gene are common in head and neck squamous cell carcinoma (HNSCC) and correlate with radioresistance. Currently, there are no clinically available therapeutic approaches targeting p53 in HNSCC. In this report, the authors propose a strategy that uses TP53 mutational status to individualize antimetabolic strategies for the potentiation of radiation toxicity in HNSCC cells.
Methods:
Glycolytic flux and mitochondrial respiration were evaluated in wild-type (wt) and mutant (mut) TP53 HNSCC cell lines. Sensitivity to external-beam radiation (XRT) was measured using a clonogenic assay.
Results:
HNSCC cells that expressed mutTP53 demonstrated radioresistance compared with HNSCC cells that expressed wtTP53. Glycolytic inhibition potentiated radiation toxicity in mutTP53-expressing, but not wtTP53-expressing, HNSCC cells. The relative sensitivity of mutTP53 HNSCC cells to glycolytic inhibition was caused by a glycolytic dependence associated with decreased mitochondrial complex II and IV activity. The wtTP53-expressing cells maintained mitochondrial reserves and were relatively insensitive to glycolytic inhibition. Inhibition of respiration using metformin increased glycolytic dependence in wtTP53-expressing cells and potentiated the effects of glycolyic inhibition on radiation toxicity.
Conclusions:
TP53 mutation in HNSCC cells was correlated with a metabolic shift away from mitochondrial respiration toward glycolysis, resulting in increased sensitivity to the potentiating effects of glycolytic inhibition on radiation toxicity. In contrast, wtTP53-expressing cells required inhibition of both mitochondrial respiration and glycolysis to become sensitized to radiation. Therefore, the authors concluded that TP53 mutational status may be used as a marker of altered tumor cell metabolism to individualize HNSCC treatment selection of specific, targeted metabolic agents that can overcome cellular resistance to radiation therapy.
Insights
TP53 mutations in head and neck cancer cells shift metabolism towards glycolysis, increasing sensitivity to radiation therapy when combined with glycolytic inhibitors. Wild-type TP53 cells require both glycolysis and respiration inhibition for radiosensitization.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Pathways
Background:
- Mutations in the tumor protein 53 (TP53) gene are frequent in head and neck squamous cell carcinoma (HNSCC) and linked to radioresistance.
- Current therapies lack specific strategies targeting p53 in HNSCC.
Purpose of the Study:
- To investigate the role of TP53 mutational status in HNSCC cell metabolism.
- To explore individualized antimetabolic strategies for potentiating radiation toxicity based on TP53 status.
Main Methods:
- Assessed glycolytic flux and mitochondrial respiration in wild-type (wt) and mutant (mut) TP53 HNSCC cell lines.
- Measured radiation sensitivity using clonogenic assays.
- Evaluated the effects of glycolytic and respiratory inhibition on radiation toxicity.
Main Results:
- Mutant TP53 HNSCC cells exhibited radioresistance compared to wt TP53 cells.
- Glycolytic inhibition enhanced radiation toxicity in mut TP53 cells due to increased glycolytic dependence and reduced mitochondrial activity.
- Wt TP53 cells were less sensitive to glycolytic inhibition alone but became sensitized when both respiration and glycolysis were inhibited.
Conclusions:
- TP53 mutation drives a metabolic shift towards glycolysis in HNSCC, enhancing sensitivity to radiation when combined with glycolytic inhibitors.
- Wt TP53 HNSCC cells necessitate dual inhibition of mitochondrial respiration and glycolysis for radiosensitization.
- TP53 mutational status can guide personalized metabolic therapies to overcome radioresistance in HNSCC.
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