Low-dose ionizing radiation exposure represses the cell cycle and protein synthesis pathways in in vitro human primary keratinocytes and U937 cell lines - PubMed (original) (raw)

. 2018 Jun 18;13(6):e0199117.

doi: 10.1371/journal.pone.0199117. eCollection 2018.

Kaori Saitoh 1, Haeun Yang 1 2, Haruki Kawashima 3, Saiko Kazuno 4, Mika Kikkawa 4, Hajime Arai 4, Takashi Miida 1, Nobuhiro Hayashi 3, Francois Niyonsaba, Keisuke Sasai 5, Yoko Tabe 1 6

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Low-dose ionizing radiation exposure represses the cell cycle and protein synthesis pathways in in vitro human primary keratinocytes and U937 cell lines

Kazumasa Sekihara et al. PLoS One. 2018.

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Abstract

The effects of the high-dose ionizing radiation used in radiotherapy have been thoroughly demonstrated in vitro and in vivo. However, the effects of low-dose ionizing radiation (LDIR) such as computed tomography-guided biopsies and X-ray fluoroscopy on skin cells remain controversial. This study investigated the molecular effects of LDIR on the human primary keratinocytes (HPKs) and U937 cells, monocytes-like cell lines. These cells were exposed to 0.1 Gray (Gy) X-ray as LDIR. The modulation of transcription was assessed using a cDNA array, and the protein expression after LDIR exposure was investigated using isobaric tags for relative and absolute quantification (iTRAQ) proteomic analysis at 24 hours. These effects were confirmed by immunoblotting analysis. The direct effects of LDIR on the U937 cells and HPKs and the bystander effects of irradiated HPKs on U937 cells were also investigated. LDIR downregulated c-Myc in both U937 cells and HPKs, and upregulated the p21WAF1/CIP1 protein expression in U937 cells along with the activation of TGFβ and protein phosphatase 2A (PP2A). In HPKs, LDIR downregulated the mTOR signaling with repression of S6 and 4EBP1 activation. Similar changes were observed as bystander effects of LDIR. Our findings suggest that LDIR inhibits protein synthesis and induces the cytokines activation associated with inflammation via direct and bystander effects, which might recapitulate the effects of LDIR in inflammated skin structures.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1

Fig 1. Molecular pathways affected by LDIR in U937 cells and HPKs.

After direct LDIR for 24 hours or in the bystander condition, the cells were subjected to lysis and immunoblot analyses. The results are representative of three independent experiments, and the intensity of each immunoblot signal compared with that of α-tubulin was quantified using ImageJ software; the quantity is shown directly under each blot.

Fig 2

Fig 2. LDIR inhibits cell growth and protein synthesis and induces bystander effects.

Cell signaling pathways affected by LDIR. LDIR downregulates c-Myc and upregulates p21 WAF1/CIP1 via stimulation of TGFβ and PP2A. PP2A also inhibits mTOR signaling with repression of S6K activation and 4EBP1 phosphorylation that resulted in decrease in protein synthesis. Furthermore, LDIR induces bystander effects through p38 MAPK activation. Directly-irradiated cells release cytokine signals that affect non-irradiated (bystander) cells.

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This work was supported by the Foundation of Strategic Research Projects in Private Universities from the MEXT, Japan grant no. S1311011 to YT. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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