High-LET Carbon and Iron Ions Elicit a Prolonged and Amplified p53 Signaling and Inflammatory Response Compared to low-LET X-Rays in Human Peripheral Blood Mononuclear Cells.

Ellina Macaeva,Arlette Michaux,Winnok H De Vos,Roel Quintens,Sarah Baatout,Nicole Averbeck,Ann Janssen,Kevin Tabury,Marjan Moreels

doi:10.3389/fonc.2021.768493

Abstract

Understanding the differences in biological response to photon and particle radiation is important for optimal exploitation of particle therapy for cancer patients, as well as for the adequate application of radiation protection measures for astronauts. To address this need, we compared the transcriptional profiles of isolated peripheral blood mononuclear cells 8 h after exposure to 1 Gy of X-rays, carbon ions or iron ions with those of non-irradiated cells using microarray technology. All genes that were found differentially expressed in response to either radiation type were up-regulated and predominantly controlled by p53. Quantitative PCR of selected genes revealed a significantly higher up-regulation 24 h after exposure to heavy ions as compared to X-rays, indicating their prolonged activation. This coincided with increased residual DNA damage as evidenced by quantitative γH2AX foci analysis. Furthermore, despite the converging p53 signature between radiation types, specific gene sets related to the immune response were significantly enriched in up-regulated genes following irradiation with heavy ions. In addition, irradiation, and in particular exposure to carbon ions, promoted transcript variation. Differences in basal and iron ion exposure-induced expression of DNA repair genes allowed the identification of a donor with distinct DNA repair profile. This suggests that gene signatures may serve as a sensitive indicator of individual DNA damage repair capacity. In conclusion, we have shown that photon and particle irradiation induce similar transcriptional pathways, albeit with variable amplitude and timing, but also elicit radiation type-specific responses that may have implications for cancer progression and treatment

Highlights

To compare the effects of high- and low-linear energy transfer (LET) radiation exposure on gene expression in human peripheral blood mononuclear cells (PBMCs), microarray analysis was performed at 8 h after exposure to 1 Gy of X-rays, carbon ions or iron ions
A similar result was obtained by Sokolov and coauthors who showed that gene expression profiles in normal human fibroblasts following g-radiation and decays of high-LET-like 125I share the majority of genes, indicating activation of similar pathways [60]
A study by Kurpinski and co-authors showed that most of the differentially expressed genes which were in common after exposure to 1 Gy of X-rays and iron ions in human mesenchymal stem cells were involved in cell cycle and DNA damage response and repair, which is in accordance with our observations [61]

Summary

Introduction

The use of charged particles is a promising modality in cancer therapy. Particle therapy, which uses focused beams of charged particles such as protons and carbon ions, has become the treatment of choice for targeting specific solid tumors [1, 2], which plays an important role in tumor management in pediatric patients [3]. The main advantage of charged particle beams is the possibility to target the tumor more precisely, while the surrounding healthy tissues receive a lower dose as compared to conventional photon radiotherapy [4]. This reduces the chance of secondary cancer development [5] and impairment of the immune system [6]. High linear energy transfer (LET) radiation, like for instance carbon ions, has a higher relative biological effectiveness (RBE) compared to conventional low-LET photon therapy [7], as particles deposit their energy in a more focused manner and result in more complex clustered DNA damage which is more lethal to the tumor cells [8] but may affect the healthy tissue. Genes involved in DNA damage repair, apoptosis, proliferation and inflammatory processes play a role in the normal tissue response to irradiation [12]

Methods

Results

Conclusion