DNA-dependent protein kinase catalytic subunit inhibitor reverses acquired radioresistance in lung adenocarcinoma by suppressing DNA repair

Abstract

Abstract. The mechanisms underlying lung cancer radioresistance remain to be fully elucidated. The DNA repair pathway is a predominant target of radiotherapy, which is considered to be involved in the acquired radioresistance of cancer cells. The present study aimed to establish a radioresistant cell model using the A549 human lung cancer cell line, and to further investigate the potential mechanisms underlying the radioresistance. The A549R radioresistant lung cancer cell variant was established by exposing the parental A549 cells to repeated γ-ray irradiation at a total dose of 60 Gy. Colony formation assays were then used to determine cell survival following γ-ray exposure. The established radioresistant cells were subsequently treated with or without the NU7026 DNA-PKcs inhibitor. The levels of DNA damage were determined by counting the number of fluorescent γ-H2AX foci in the cells. The cellular capacity for DNA repair was assessed using antibodies for the detection of various DNA repair pathway proteins. The radioresistant sub-clones exhibited significantly decreased survival following NU7026 treatment, compared with the parental cells, as determined by colony formation assays (P<0.05), and this finding was found to be dose-dependent. Treatment with the DNA-dependent protein kinase (DNA-PK) inhibitor significantly reduced γ-H2AX foci formation (P<0.05) following acute radiation exposure in the radioresistant sub-clones, compared with the parental control cells. The decreased levels of γ-H2AX were accompanied by an increase in the percentage of apoptotic cells in the radioresistant cell line following post-radiation treatment with the DNA-PKcs inhibitor. The expression levels of proteins associated with the DNA repair pathway were altered markedly in the cells treated with NU7026. The results of the present study suggested that radioresistance may be associated with enhanced DNA repair following exposure to radiation, resulting in reduced apoptosis. Therefore, the quantity of γ-H2AX determines the radioresistance of cells. The DNA repair pathway is important in mediating radioresistance, and treatment with the DNA-PKcs inhibitor, NU7026 restored the acquired radiation resistance.

Knockdown of SMAD3 inhibits the growth and enhances the radiosensitivity of lung adenocarcinoma via p21 in vitro and in vivo

“…However, lung adenocarcinoma is not highly sensitive to radiation, and the progressive tolerance of tumor cells during irradiation often causes local recurrence and poor prognosis [5]. Because the sensitivity of tumor cells is a key factor in the efficacy of radiotherapy, it is necessary to identify critical molecules related to the radiosensitivity of lung adenocarcinoma, as well as the factors linked to rapid cell growth.…”

The nomogram for the prediction of overall survival in patients with metastatic lung adenocarcinoma undergoing primary site surgery: A retrospective population-based study

“…An analysis of a previous meta-analysis reported that postoperative chest radiotherapy has an overall negative effect on survival, resulting in a 21.3% relative increase in odds of dying [hazard ratio (HR)1.21 (95% CI 1.08-1.34)]; meaning, an absolute reduction of 7% in survival from 55% to 48% at 2 years owing to the decrease in survival rates possible (43, 44). One of the possible reasons for this finding may be the increase in intrinsic and acquired radioresistance among patients suffering from cancers, which has led to a decrease in the success of their treatment (45).LUAD is not particularly sensitive to radiation, and thus, tumor cells are capable of developing a tolerance to radiation, resulting in local recurrences and poor prognoses (46).…”

Identification of Radiotherapy-Associated Genes in Lung Adenocarcinoma by an Integrated Bioinformatics Analysis Approach

“…As one of mainstream cancer therapies, RT has a good effect in a variety of tumors ( De Ruysscher et al, 2019 ; Sia et al, 2020 ). However, it is not so effective for several cancers, including LUAD ( Li et al, 2015 ). In the clinic, there are many NSCLC patients who are failed to achieve a cure after surgery.…”