The balance between NRF2/GSH antioxidant mediated pathway and DNA repair modulates cisplatin resistance in lung cancer cells

• Published in: Scientific reports Vol. 9; no. 1; pp. 17639 - 11
• Main Authors: Silva, Matheus Molina, Rocha, Clarissa Ribeiro Reily, Kinker, Gabriela Sarti, Pelegrini, Alessandra Luiza, Menck, Carlos Frederico Martins
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.11.2019; Nature Publishing Group
• Subjects: 13/1; 13/31; 38/39; 38/77; 38/89; 631/337/1427/1430; 631/67/1059/2326; 631/67/1612/1350; 631/92/147; 692/53/2422; 82/80; A549 Cells - drug effects; A549 Cells - metabolism; Antineoplastic Agents - therapeutic use; Antioxidants; Antioxidants - metabolism; Biomarkers, Tumor - metabolism; Blotting, Western; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Death - drug effects; Cell Line, Tumor; Cell viability; Chemotherapy; Cisplatin; Cisplatin - therapeutic use; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; DNA Repair - drug effects; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Flow Cytometry; Gene expression; Glutathione; Glutathione - metabolism; Humanities and Social Sciences; Humans; Intracellular levels; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Medical prognosis; multidisciplinary; NF-E2-Related Factor 2 - metabolism; Non-small cell lung carcinoma; Real-Time Polymerase Chain Reaction; Science; Science (multidisciplinary); Signal Transduction - drug effects; Small cell lung carcinoma; Survival; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-54065-6

Lung cancer patients face a dismal prognosis mainly due to the low efficacy of current available treatments. Cisplatin is the first-line chemotherapy treatment for those patients, however, resistance to this drug is a common and yet not fully understood phenomenon. Aiming to shed new light into this puzzle, we used established normal and malignant lung cell lines displaying different sensitivity towards cisplatin treatment. We observed a negative correlation between cell viability and DNA damage induction upon cisplatin treatment. Interestingly, drug sensitivity in those cell lines was not due to either difference on DNA repair capacity, or in the amount of membrane ion channel commonly used for cisplatin uptake. Also, we noted that glutathione intracellular levels, and expression and activity of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) were determinant for cisplatin cytotoxicity. Remarkably, analysis of gene expression in non-small cell lung cancer patients of the TCGA data bank revealed that there is a significant lower overall survival rate in the subset of patients bearing tumors with unbalanced levels of NRF2/KEAP1 and, as consequence, increased expression of NRF2 target genes. Thus, the results indicate that NRF2 and glutathione levels figure as important cisplatin resistance biomarkers in lung cancer.