Investigating Molecular Determinants of Cancer Cell Resistance to Ionizing Radiation Through an Integrative Bioinformatics Approach.

Halil Ibrahim Toy,Gökhan Karakülah,Athanasia Pavlopoulou,Panagiota I Kontou,Alexandros G Georgakilas,Hani Alotaibi

doi:10.3389/fcell.2021.620248

Abstract

Eradication of cancer cells through exposure to high doses of ionizing radiation (IR) is a widely used therapeutic strategy in the clinical setting. However, in many cases, cancer cells can develop remarkable resistance to radiation. Radioresistance represents a prominent obstacle in the effective treatment of cancer. Therefore, elucidation of the molecular mechanisms and pathways related to radioresistance in cancer cells is of paramount importance. In the present study, an integrative bioinformatics approach was applied to three publicly available RNA sequencing and microarray transcriptome datasets of human cancer cells of different tissue origins treated with ionizing radiation. These data were investigated in order to identify genes with a significantly altered expression between radioresistant and corresponding radiosensitive cancer cells. Through rigorous statistical and biological analyses, 36 genes were identified as potential biomarkers of radioresistance. These genes, which are primarily implicated in DNA damage repair, oxidative stress, cell pro-survival, and apoptotic pathways, could serve as potential diagnostic/prognostic markers cancer cell resistance to radiation treatment, as well as for therapy outcome and cancer patient survival. In addition, our findings could be potentially utilized in the laboratory and clinical setting for enhancing cancer cell susceptibility to radiation therapy protocols.

Highlights

Radiation therapy or radiotherapy (RT) represents one of the optimal, most widely used modalities in the treatment of multiple cancers, either alone or combined with other curative anti-cancer modalities like chemotherapy (Delaney et al, 2005; Begg et al, 2011) or immunotherapy (Tang et al, 2014; Schoenhals et al, 2016)
We employed an integrative bioinformatics approach to analyze transcriptomic data regarding the molecular determinants of cancer cell radioresistance
On the basis of our findings, both solid and hematologic cancer cells likely depend on similar mechanisms to confer resistance to ionizing radiation (IR) (i.e., damage response and repair (DDR/R) and cell survival)

Summary

Introduction

Radiation therapy or radiotherapy (RT) represents one of the optimal, most widely used modalities in the treatment of multiple cancers, either alone or combined with other curative anti-cancer modalities like chemotherapy (Delaney et al, 2005; Begg et al, 2011) or immunotherapy (Tang et al, 2014; Schoenhals et al, 2016). Cancer cells have the capacity to develop incredible tolerability and resistance to RT, thereby evading death. Radioresistance represents a major limiting factor in the effective treatment of different types of cancers. The response of tumor cells to radiation depends both on the resistance mechanisms of the cells and on the accelerated repopulation of the tumor bulk by cells that have developed further radioresistance (Pavlopoulou et al, 2016, 2017). As noted in previous studies, the genes that are differentially expressed (either up- or downregulated) between radioresistant (RR) and radiosensitive (RR) cancer cells are generally implicated in DNA damage response and repair (DDR/R) pathways, apoptosis, hypoxia, or response to oxidative stress, etc. The complexity of radiation resistance mechanisms suggests the involvement of different and diverse biological mechanisms

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Discussion

Conclusion