Background: Tumor cells, able to provide sufficient ATP in response to irradiation, promote DNA damage repair and are therefore likely to survive the therapy. The aim of the present study was to better understand the metabolic energy response of HNSCC (head and neck squamous cell carcinoma) cells to irradiation, which could help to identify therapeutic weak points. Material and methods: Three HPV^neg and three HPV^pos HNSCC cell lines were evaluated regarding their metabolic response after irradiation with photons. For this, mitochondrial (mito) and glycolytic (glyco) ATP production as well as the mito/glyco ATP ratio were evaluated with the Seahorse XFe96 Extracellular Flux Analyzer 2, 6, 10 and 24h after irradiation with 4 and 8 Gy. Results: Irradiation of all 6 HNSCC cell lines with 8 Gy photons, resulted in a significant drop of mitoATP production at 2h, followed by a significant rise at 6 and 10h and a subsequent drop at 24h. The mito/glyco ATP ratio at 8 Gy exhibited a rise until 6h with a subsequent drop until 24h after irradiation. When comparing HPV^neg with HPV^pos HNSCC cell lines, both groups responded with an early drop in mitoATP production at 2h, a prominent elevation at 6 and 10h and a strong drop below control levels at 24h. Relevant changes in glycoATP production were only noted in the HPV^neg but not HPV^pos group. Accordingly, the mito/glyco ATP ratio was significantly higher in the HPV^pos group after irradiation with 8 Gy. Discussion: Similarly to our previous observations on non-irradiated HNSCC cells, irradiated HPV^pos cells, in sharp contrast to irradiated HPV^neg cells, use significantly more oxidative phosphorylation (mito) over glycolysis (glyco) for energy production, which could make HPV^pos cells particularly sensitive to hypoxic conditions.

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