title: Proteomic Analysis Implicates Dominant Alterations of RNA Metabolism and the Proteasome Pathway in the Cellular Response to Carbon-Ion Irradiation.
abstract: Radiotherapy with heavy ions is considered advantageous compared to irradiation with photons due to the characteristics of the Braggs peak and the high linear energy transfer (LET) value. To understand the mechanisms of cellular responses to different LET values and dosages of heavy ion radiation, we analyzed the proteomic profiles of mouse embryo fibroblast MEF cells exposed to two doses from different LET values of heavy ion 12C. Total proteins were extracted from these cells and examined by Q Exactive with Liquid Chromatography (LC)-Electrospray Ionization (ESI) Tandem MS (MS/MS). Using bioinformatics approaches, differentially expressed proteins with 1.5 or 2.0-fold changes between different dosages of exposure were compared. With the higher the dosage and/or LET of ion irradiation, the worse response the cells were in terms of protein expression. For instance, compared to the control (0 Gy), 771 (20.2%) proteins in cells irradiated at 0.2 Gy of carbon-ion radiation with 12.6 keV/μm, 313 proteins (8.2%) in cells irradiated at 2 Gy of carbon-ion radiation with 12.6 keV/μm, and 243 proteins (6.4%) in cells irradiated at 2 Gy of carbon-ion radiation with 31.5 keV/μm exhibited changes of 1.5-fold or greater. Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Munich Information Center for Protein Sequences (MIPS) analysis, and BioCarta analysis all indicated that RNA metabolic processes (RNA splicing, destabilization and deadenylation) and proteasome pathways may play key roles in the cellular response to heavy-ion irradiation. Proteasome pathways ranked highest among all biological processes associated with heavy carbon-ion irradiation. In addition, network analysis revealed that cellular pathways involving proteins such as Col1a1 and Fn1 continued to respond to high dosages of heavy-ion irradiation, suggesting that these pathways still protect cells against damage. However, pathways such as those involving Ikbkg1 responded better at lower dosages than at higher dosages, implying that cell damage would occur when the networks involving these proteins stop responding. Our investigation provides valuable proteomic information for elucidating the mechanism of biological effects induced by carbon ions in general.
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiation Biology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiation Biology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiation Biology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Da-Fei
authors.initials: DF
authors.lastname: Xie
authors.affiliation: Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiation Biology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Liu
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiation Biology, Beijing Institute of Radiation Medicine, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: China Institute of Atomic Energy, Beijing 102413, China.
authors.forename: Li
authors.initials: L
authors.lastname: Sui
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiation Biology, Beijing Institute of Radiation Medicine, Beijing, China.|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, School of Radiation Medicine and Protection, Soochow University, Suzhou, China.
authors.forename: Man
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: iBioinfo Groups, Lexington, Massachusetts 02421, United States of America.|Department of Neuroregeneration, Nantong University, Nantong, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Radiation Toxicology and Oncology, Beijing Key Laboratory for Radiation Biology, Beijing Institute of Radiation Medicine, Beijing, China.|Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, School of Radiation Medicine and Protection, Soochow University, Suzhou, China.
authors.forename: Ping-Kun
authors.initials: PK
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002244:Carbon / Q000494:pharmacology*; D002460:Cell Line; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism* / Q000528:radiation effects*; D063193:Heavy Ion Radiotherapy; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D040901:Proteomics; D012313:RNA / Q000378:metabolism*
chemical_list: D012313:RNA; D002244:Carbon; D046988:Proteasome Endopeptidase Complex