Abstract
ObjectiveTo analyze the effect of carbon ion (12C6+) radiation may induce bystander effect on A549 cell metastasis and metabonomics.MethodsA549 cell was irradiated with carbon ion to establish the clone survival model and the transwell matrix assay was applied to measure the effect of carbon ion on cell viability, migration, and invasion, respectively. Normal human embryonic lung fibroblasts (WI-38) were irradiated with carbon ions of 0 and 2 Gy and then transferred to A549 cell co-culture medium for 24 h. The migration and invasion of A549 cells were detected by the Transwell chamber. The analysis of metabonomic information in transfer medium by liquid phase mass spectrometry (LC-MS), The differential molecules were obtained by principal pomponent analysis (PCA) and the target proteins of significant differences (p = 1.7 × 10−3) obtained by combining with the STICH database. KEGG pathway was used to analyze the enrichment of the target protein pathway.ResultsCompared with 0 Gy, the colony formation, migration, and invasion of A549 cells were significantly inhibited by carbon ion 2 and 4 Gy irradiation, while the inhibitory effect was not significant after 1 Gy irradiation. Compared with 0 Gy, the culture medium 24 h after carbon ion 2 Gy irradiation significantly inhibited the metastasis of tumor cells (p = 0.03). LC-MS analysis showed that 23 differential metabolites were obtained in the cell culture medium 24 h after carbon ion 0 and 2 Gy irradiation (9 up-regulated and 14 down-regulated). Among them, two were up-regulated and two down-regulated (p = 2.9 × 10−3). 41 target proteins were corresponding to these four differential molecules. Through the analysis of the KEGG signal pathway, it was found that these target molecules were mainly enriched in purine metabolism, tyrosine metabolism, cysteine and methionine metabolism, peroxisome, and carbon metabolism. Neuroactive ligand-receptor interaction, calcium signaling pathway, arachidonic acid metabolism, and Fc epsilon RI signaling pathway.ConclusionThe bystander effect induced by 2 Gy carbon ion radiation inhibits the metastasis of tumor cells, which indicates that carbon ions may change the metabolites of irradiated cells, so that it may indirectly affect the metabolism of tumor cell growth microenvironment, thus inhibiting the metastasis of malignant tumor cells.
Highlights
In 2018, there were 18.1 million new cases of cancer worldwide, of which the incidence of lung cancer was 11.6% and the mortality rate was 18.4% [1]
We evaluated the effect of carbon ion beams on the colony formation ability of A549 cells
After 1 Gy irradiation, A549 cell proliferation was significantly inhibited at 24 h, and this inhibition increased in a dose-dependent manner
Summary
In 2018, there were 18.1 million new cases of cancer worldwide, of which the incidence of lung cancer was 11.6% and the mortality rate was 18.4% [1]. The study of proton targeting cancer cells and unirradiated normal fibroblasts found an induced bi-directional bystander effect, and RIBE was detected in vitro, 3D tissues and mouse models [6].Growing evidence show that bystander responses can be regulated by four mechanisms-(i) gap junction intercellular communication (ii) communication of soluble factors released by irradiated cells or organs (iii) clastogenic factors and exosomes [7, 8]. It has been found that reactive oxygen species (ROS) [9], superoxide dismutase (SOD), nitric oxide (NO) [10], cyclooxygenase 2 (COX2), CD95 ligand (Fals), transforming growth factor-b1 (TGFb1), and tumor necrosis factor-a(TNFa) [11] play an important roles in RIBE Among all these factors, some are soluble factors (TGFb1 and TNF-a), some are exosome released factors (Fals), others are common factors of both (ROS, SOD, NO, and COX2), are very similar effect to RIBE. The studies on cytokine signal transduction and production of reactive oxygen species and nitrogen species are relatively clear [17]
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