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

Date Published: June 18, 2018

Publisher: Public Library of Science

Author(s): Kazumasa Sekihara, Kaori Saitoh, Haeun Yang, Haruki Kawashima, Saiko Kazuno, Mika Kikkawa, Hajime Arai, Takashi Miida, Nobuhiro Hayashi, Keisuke Sasai, Yoko Tabe, Gayle E. Woloschak.

http://doi.org/10.1371/journal.pone.0199117

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.

Partial Text

Epidemiological and toxicological studies have examined the deleterious effects of radiation exposure in human health. High-dose ionizing radiation clearly causes harmful consequences for humans. By contrast, the risk of low-dose ionizing radiation (LDIR) is still unclear. The stochastic risk of LDIR (i.e., <0.1 Sv) is derived by extrapolation from data obtained for high-dose radiation exposure using a linear-no-threshold (LNT) model [1]. A recent epidemiological study demonstrated that the data from atomic bomb survivors supported the LNT model [2]. However, the health effects of LDIR exposure remain to be explored due to the confounding factors related to individual variability, life style, and genetic background [3, 4]. There is increasing concern regarding the health risks arising from LDIR exposure in medical diagnostics and radiation therapy. For example, computed tomography (CT) is a valuable diagnostic imaging technique, but its overuse raises concerns about the potential risks of iatrogenic cancers [5–7]. CT-guided interventional procedures result in greater dose exposure than a routine CT and have a higher risk [8][9]. This study demonstrated several findings: (1) the U937 cells, mimicking skin-infiltrating monocytes, released inflammatory cytokines after LDIR; (2) the interactions between U937 cells and irradiated neighboring keratinocytes in LDIR exposure; and (3) LDIR also inhibited the ribosomal biogenesis in keratinocytes and U937 cells in in vitro.   Source: http://doi.org/10.1371/journal.pone.0199117

 

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