Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common form of cancer worldwide. Radiotherapy, with or without surgery, represents the major approach to curative treatment. However, not all tumors are equally sensitive to irradiation. It is therefore of interest to apply newer system biology approaches (e.g., metabolic profiling) in squamous cancer cells with different radiosensitivities in order to provide new insights on the mechanisms of radiation response. In this study, two cultured HNSCC cell lines from the same donor, UM-SCC-74A and UM-SCC-74B, were first genotyped using Short Tandem Repeat (STR), and assessed for radiation response by the means of clonogenic survival and growth inhibition assays. Thereafter, cells were cultured, irradiated and collected for subsequent metabolic profiling analyses using liquid chromatography-mass spectrometry (LC-MS). STR verified the similarity of UM-SCC-74A and UM-SCC-74B cells, and three independent assays proved UM-SCC-74B to be clearly more radioresistant than UM-SCC-74A. The LC-MS metabolic profiling demonstrated significant differences in the intracellular metabolome of the two cell lines before irradiation, as well as significant alterations after irradiation. The most important differences between the two cell lines before irradiation were connected to nicotinic acid and nicotinamide metabolism and purine metabolism. In the more radiosensitive UM-SCC-74A cells, the most significant alterations after irradiation were linked to tryptophan metabolism. In the more radioresistant UM-SCC-74B cells, the major alterations after irradiation were connected to nicotinic acid and nicotinamide metabolism, purine metabolism, the methionine cycle as well as the serine, and glycine metabolism. The data suggest that the more radioresistant cell line UM-SCC-74B altered the metabolism to control redox-status, manage DNA-repair, and change DNA methylation after irradiation. This provides new insights on the mechanisms of radiation response, which may aid future identification of biomarkers associated with radioresistance of cancer cells.
Highlights
Every year more than half a million new cases of squamous cell carcinoma of the head and neck (HNSCC) are reported [1], which makes it the 6th most common type of cancer worldwide [2]
We investigate the relationship between radiation response and the metabolome of Head and neck squamous cell carcinoma (HNSCC) in a unique model system, using two HNSCC cell lines from the same donor but with different radiosensitivity
UM-SCC74B cells were significantly less affected by radiation, where a radiation dose of 2 Gy resulted in a normalized spheroid size of 84 ± 5 (SEM)% of unirradiated controls, compared to 44 ± 3% for UM-SCC-74A spheroids
Summary
Every year more than half a million new cases of squamous cell carcinoma of the head and neck (HNSCC) are reported [1], which makes it the 6th most common type of cancer worldwide [2]. HNSCC is on average only moderately radiosensitive, which means that radiotherapy often must be given to such an extent that it approaches the maximum tolerated dose for the surrounding normal tissue. This may cause substantial acute and late toxicities, resulting in significant morbidity and altered quality of life [8]. There is a great need for individualized radiotherapy treatment approaches in HNSCC, to aid in predicting and monitoring tumor response to radiotherapy before, during, and after treatment. This requires new insights on the mechanisms of radiation response, novel markers to predict tumor response to radiotherapy, as well as potential treatment targets to enhance radiation-sensitivity
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