Gene Profiling Characteristics of Radioadaptive Response in AG01522 Normal Human Fibroblasts

Abstract

Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose.

Low‐dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics

“…118 Using the same method, another study revealed that miRNAs related to cell communication and intercellular signaling transduction played important roles after normal human fibroblasts were exposed to LDR. 119 Overall, many studies have confirmed that LDR induces different biological effects between normal and cancer cells (Table 1). However, a clear molecular mechanism responsible for the differences in LDR-induced biological effects in normal and cancer cells has yet to be found.…”

Global Gene Expression Alterations as a Crucial Constituent of Human Cell Response to Low Doses of Ionizing Radiation Exposure

“…However, the rather limited number of participants enrolled in these studies warrants further studies to validate these findings in larger prospective cohorts of human subjects. Also, the phenomenon of RAR at the transcriptional level was recently examined in the AG01522 human fibroblasts first exposed to 5 cGy priming dose and then followed by 2 Gy challenging dose of X-rays [ 59 ]. Both mRNA and microRNA microarray analyses were performed and the differentially expressed genes were identified using bioinformatics approaches.…”

Non-induction of radioadaptive response in zebrafish embryos by neutrons

“…For instance, DNA repair protein DIR1 and a base excision repair endonuclease APE1 were reported to be involved in RAR [ 60 – 62 ]. DNA-PK, TP53 and ATM, which were involved in DNA damage recognition and signaling, were also shown to be involved in RAR [ 63 – 65 ], and the ATM-p53 signal transduction pathway governing the DNA repair system and the cell cycle regulation system were considered the most important mediators of the radioadaptive response [ 64 , 65 ]. Interestingly, the requirement of de novo protein synthesis was implied in RAR induction [ 66 , 67 ].…”