Radiation-induced DNA damage response and resistance in colorectal cancer stem-like cells

Abstract

Purpose: Radiation therapy is an integral part of current treatment modality for colorectal cancer. Recent studies have revealed the presence of cancer stem-like cells (CSCs) population, in different tumors are responsible for therapeutic resistance and disease relapse, including colorectal cancer with poorer survival rate. Hence, characterization of the effect of Ionizing Radiation (IR) in colorectal cancer may serve to explain possible mechanisms. Material and methods: Parental HCT116 and HCT-15 cells and derived colonospheres were irradiated and dose was optimized based on cell survival assay and cell cycle analysis. DNA damage response (DDR) was elucidated by γH2AX foci formation, COMET assay, and ATM, p-ATM, ERCC1 expression post-treatment. The expression level of developmental marker (β-catenin), CSC markers (CD44, KLF4) and telomeric components (TRF2, RAP1, hTERT) were evaluated. Results: We observed cell survival was more in colonospheres post-irradiation and also exhibited decreased γH2AX foci, olive tail moment, increased ERCC1, and p-ATM expression than its parental counterpart which corresponds to efficient DDR. Differential expression of developmental marker, CSC markers, and telomeric components were observed after irradiation. Conclusion: This study highlighted the presence of CSC phenotype in colonospheres having increased DNA repair capacity. Differential expression of developmental marker, CSC markers and telomeric components between parental and colonospheres may contribute in radio-resistance property of CSCs.

Keywords: Ionizing radiation; cancer stem-like cells; genomic instability; radiotherapy; shelterin component.