Introduction. Radiotherapy is one of the mainstays of treatment for squamous cell carcinoma. Identifying tumour markers able to predict tumour sensitivity to radiotherapy could enable patient/tumour specific treatment targeting and/or dose modification. In a recent study we demonstrated that high levels of EGFR and cyclin D1 were associated with disease recurrence after radiotherapy for patients with T2 laryngeal cancer.1 The aim of this study was to investigate this relationship in a panel of cell lines derived from laryngeal squamous cell carcinomas (LSCC). Methods. Six LSCC cell lines were exposed to 2Gy of gamma irradiation from a 147Caesium source. Following irradiation, a clonogenic assay was used to define the relative radiosensitivity (SF2) of each cell line. Western blot analysis, followed by densitometry measurement, was used to determine the relative expression of EGFR and cyclin D1 in each cell line. Results. Levels of EGFR and cyclin D1 were individually not strongly predictive for radiosensitivity. However, cell lines with a combination of high expression of EGFR and low expression of cyclin D1 were found to correlate strongly with a radioresistant phenotype (P = 0.95). Conclusions. This study accords with previous evidence that the cyclin D1/ EGFR axis is important in determining radiation susceptibility. However, in contrast to previous work we found that low, as opposed to high levels of cyclin D1, were associated with radioresistance. Our studies provide an opportunity for functional investigation of the roles of EGFR and cyclin D1 in determining radioresistance in LSCC cells.
Objectives. Radiotherapy is one of the mainstays of treatment for squamous cell carcinoma of the larynx but is often associated with severe morbidity. Providing patients with targeted treatment according to tumour type is a major goal of clinicians treating the disease. It has previously been shown that p53 is a critical mediator of radiation response and thus we investigated its influence on radiosensitivity and also whether Nutlin‐3 (the small molecule inhibitor of p53/MDM2 interaction) could radiosensitise tumours. Methods. Seven cell lines derived exclusively from patients with laryngeal carcinoma and with defined p53 status (determined by direct sequencing of exons 2–11 and intron/exon boundaries) were examined. Radiosensitivity was determined by clonogenic assays following treatment with gamma irradiation in the presence and absence of Nutlin‐3. Flow cytometry was used to determine cell cycle characteristics and the levels of apoptosis and senescence were also measured. Results. Cells with p53 homozygous mutations were relatively radiosensitive (SF2 < 20%). Cell lines with wild‐type p53, heterozygous and homozygous non‐sense mutations were relatively radioresistant (SF2 > 60%). Wild‐type p53 cells were made significantly more radiosensitive after treatment with Nutlin‐3. Neither apoptosis nor cell cycle responses corresponded with radiosensitivity. Interestingly, cells that displayed senescence were radioresistant whereas those that did not were radiosensitive suggesting a possible role for senescence in determining radiosensitivity. Conclusions. This is the first study to demonstrate that Nutlin‐3 may be an effective radiosensitiser in laryngeal cancer cell lines with wild‐type p53. The clinical application of Nutlin‐3 might improve survival rates or reduce therapeutic doses in these patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.