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Broad phenotypic changes associated with gain of radiation resistance in head and neck squamous cell cancer.

ABSTRACT: The central issue of resistance to radiation remains a significant challenge in the treatment of cancer despite improvements in treatment modality and emergence of new therapies. To facilitate the identification of molecular factors that elicit protection against ionizing radiation, we developed a matched model of radiation resistance for head and neck squamous cell cancer (HNSCC) and characterized its properties using quantitative mass spectrometry and complementary assays.Functional network analysis of proteomics data identified DNA replication and base excision repair, extracellular matrix-receptor interaction, cell cycle, focal adhesion, and regulation of actin cytoskeleton as significantly up- or downregulated networks in resistant (rSCC-61) HNSCC cells. Upregulated proteins in rSCC-61 included a number of cytokeratins, fatty acid synthase, and antioxidant proteins. In addition, the rSCC-61 cells displayed two unexpected features compared with parental radiation-sensitive SCC-61 cells: (i) rSCC-61 had increased sensitivity to Erlotinib, a small-molecule inhibitor of epidermal growth factor receptor; and (ii) there was evidence of mesenchymal-to-epithelial transition in rSCC-61, confirmed by the expression of protein markers and functional assays (e.g., Vimentin, migration).The matched model of radiation resistance presented here shows that multiple signaling and metabolic pathways converge to produce the rSCC-61 phenotype, and this points to the function of the antioxidant system as a major regulator of resistance to ionizing radiation in rSCC-61, a phenomenon further confirmed by analysis of HNSCC tumor samples.The rSCC-61/SCC-61 model provides the opportunity for future investigations of the redox-regulated mechanisms of response to combined radiation and Erlotinib in a preclinical setting.

SUBMITTER: Bansal N

PROVIDER: S-EPMC4060837 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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Broad phenotypic changes associated with gain of radiation resistance in head and neck squamous cell cancer.

Bansal Nidhi N Mims Jade J Kuremsky Jeffrey G JG Olex Amy L AL Zhao Weiling W Yin Leimiao L Wani Revati R Qian Jiang J Center Brian B Marrs Glen S GS Porosnicu Mercedes M Fetrow Jacquelyn S JS Tsang Allen W AW Furdui Cristina M CM

Antioxidants & redox signaling 20140410 2

<h4>Aims</h4>The central issue of resistance to radiation remains a significant challenge in the treatment of cancer despite improvements in treatment modality and emergence of new therapies. To facilitate the identification of molecular factors that elicit protection against ionizing radiation, we developed a matched model of radiation resistance for head and neck squamous cell cancer (HNSCC) and characterized its properties using quantitative mass spectrometry and complementary assays.<h4>Resu ...[more]

PMID: 24597745

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Project description:Exosomes are nanometer-sized extracellular vesicles that are believed to function as intercellular communicators. Here, we report that exosomes are able to modify the radiation response of the head and neck cancer cell lines BHY and FaDu. Exosomes were isolated from the conditioned medium of irradiated as well as non-irradiated head and neck cancer cells by serial centrifugation. Quantification using NanoSight technology indicated an increased exosome release from irradiated compared to non-irradiated cells 24 hours after treatment. To test whether the released exosomes influence the radiation response of other cells the exosomes were transferred to non-irradiated and irradiated recipient cells. We found an enhanced uptake of exosomes isolated from both irradiated and non-irradiated cells by irradiated recipient cells compared to non-irradiated recipient cells. Functional analyses by exosome transfer indicated that all exosomes (from non-irradiated and irradiated donor cells) increase the proliferation of non-irradiated recipient cells and the survival of irradiated recipient cells. The survival-promoting effects are more pronounced when exosomes isolated from irradiated compared to non-irradiated donor cells are transferred. A possible mechanism for the increased survival after irradiation could be the increase in DNA double-strand break repair monitored at 6, 8 and 10 h after the transfer of exosomes isolated from irradiated cells. This is abrogated by the destabilization of the exosomes. Our results demonstrate that radiation influences both the abundance and action of exosomes on recipient cells. Exosomes transmit prosurvival effects by promoting the proliferation and radioresistance of head and neck cancer cells. Taken together, this study indicates a functional role of exosomes in the response of tumor cells to radiation exposure within a therapeutic dose range and encourages that exosomes are useful objects of study for a better understanding of tumor radiation response.

Project description: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.

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Broad phenotypic changes associated with gain of radiation resistance in head and neck squamous cell cancer.

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Broad phenotypic changes associated with gain of radiation resistance in head and neck squamous cell cancer.

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