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.
Highlights
Radiotherapy using heavy ions beams or protons is becoming an important component of malignant tumor therapy [1, 2]
The increased biological efficacy of high linear energy transfer (LET) is usually described as the quantity of relative biological effectiveness (RBE) compared to low-LET γ- or X-ray irradiation, which is dependent on the LET value [7, 8]
Network analysis revealed that cellular pathways involving proteins such as Col1a1 and Fn1 continue to respond to high dosages of heavy-ion irradiation, suggesting that these pathways continue to protect cells against damage
Summary
Radiotherapy using heavy ions beams or protons is becoming an important component of malignant tumor therapy [1, 2]. The increased therapeutic ratio permits dose escalation within the tumor, resulting in improved tumor control Another advantage is the high linear energy transfer (LET) characteristics of heavy-ion beams [4]. High-LET radiation, such as carbon-ion beam, deposits higher energy in tissues and causes greater damage than low-LET γ- or X-ray irradiation [4, 5]. The increased biological efficacy of high LET is usually described as the quantity of relative biological effectiveness (RBE) compared to low-LET γ- or X-ray irradiation, which is dependent on the LET value [7, 8]. The ratio of G2/M-arrested cells after high-LET irradiation at doses resulting in 1% cellular survival were 47, 81, and 78% for carbon-, neon-, and iron-ion radiation, respectively [9].
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