The Possible Role of Mitochondrial ATM, CDK-1, and RAN Expression in the Radioresistance of Human Lung Adenocarcinoma A549 Cells

Background/aim: Radiotherapy (RT) is a widely used treatment for non-small cell lung cancer (NSCLC), one of the most prevalent cancers globally. However, radioresistance (RR) remains a significant challenge, often leading to RT failure. The primary driver of RR is the enhanced DNA repair capability of tumor cells. Understanding the mechanisms underlying RR in NSCLC is essential for developing more effective therapeutic strategies. The ataxia-telangiectasia mutated (ATM) protein kinase is pivotal in responding to DNA double-strand breaks caused by RT. Additionally, cyclin-dependent kinase 1 (CDK1) and Ras-related nuclear protein (RAN) are crucial regulators of mitotic entry, G2 arrest, DNA repair, and cell cycle progression. Although these proteins are present in both cytosolic and mitochondrial forms, their specific roles in radiation response and RR remain poorly understood. Materials and methods: In this study, A549 cells were exposed to a single 5 Gy dose of ionizing radiation (IR) and analyzed at baseline and on days 1, 3, and 5 post-IR. The expression levels of ATM, CDK1, and RAN in cytosolic and mitochondrial fractions were assessed using immunohistochemical and Western blot analyses. Results: In immunohistochemical evaluations, ATM, CDK1, and RAN immunoreactivities A549 cancer cells were found to increase markedly on the 1st day, decreased on the 3rd day, and approached control group on the 5th day. Mitochondrial expressions of all three proteins increased significantly on day 1 but declined markedly by day 5. Conversely, altered cytosolic expressions returned to baseline levels by day 5. Conclusion: These results suggest that the early upregulation of mitochondrial ATM, CDK1, and RAN contributes to adaptive RR in A549 cancer cells, offering potential targets for overcoming RT resistance.