Abstract
Radiation therapy for head and neck cancer causes damage to the surrounding salivary glands, resulting in salivary gland hypofunction and xerostomia. Current treatments do not provide lasting restoration of salivary gland function following radiation; therefore, a new mechanistic understanding of the radiation-induced damage response is necessary for identifying therapeutic targets. The purpose of the present study was to investigate the metabolic phenotype of radiation-induced damage in parotid salivary glands by integrating transcriptomic and metabolomic data. Integrated data were then analyzed to identify significant gene-metabolite interactions. Mice received a single 5 Gy dose of targeted head and neck radiation. Parotid tissue samples were collected 5 days following treatment for RNA sequencing and metabolomics analysis. Altered metabolites and transcripts significantly converged on a specific region in the metabolic reaction network. Both integrative pathway enrichment using rank-based statistics and network analysis highlighted significantly coordinated changes in glutathione metabolism, energy metabolism (TCA cycle and thermogenesis), peroxisomal lipid metabolism, and bile acid production with radiation. Integrated changes observed in energy metabolism suggest that radiation induces a mitochondrial dysfunction phenotype. These findings validated previous pathways involved in the radiation-damage response, such as altered energy metabolism, and identified robust signatures in salivary glands, such as reduced glutathione metabolism, that may be driving salivary gland dysfunction.
Highlights
The American Cancer Society estimates that over 53,000 new cases of head and neck cancer are reported each year in the United States [1]
At 5 days post radiation, a clear distinction was observed between the metabolite profiles of the irradiated and untreated groups in the principal component analysis (PCA; Fig. 1A) and orthogonal partial least squares discriminant analysis (OPLS-DA; Fig. 1B)
Out of the 54 metabolites identified from the significant-features plot (S-plot), five were not annotated to Kyoto Encyclopedia of Genes and Genomes (KEGG), Human Metabolome Database (HMDB), or PubChem: 1-dihomo-linolenylglycerol (20:3), 1-heptadecenoylglycerol (17:1), equol sulfate, glycosyl ceramide (d18:1/20:0, d16:1/22:0), and glycosyl ceramide (d18:2/24:1, d18:1/24:2) (Supplemental Table S2)
Summary
The American Cancer Society estimates that over 53,000 new cases of head and neck cancer are reported each year in the United States [1]. Radiation therapy is part of the standard of care for these types of cancers, but it causes irreversible damage to the surrounding salivary glands resulting in a significant loss of physiological function [2]. This damage leads to chronic hyposalivation and xerostomia, diminishing the quality of life of these patients with cancer [3, 4]. No study has investigated the metabolic alterations caused by radiation-induced damage to salivary glands
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
