Abstract
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.
Highlights
Cancer is one of the main causes of morbidity and mortality worldwide, with a total annual economic costs of approximately US$ 1.16 trillion, and the number of cases are expected to rise 70% over the two decades[1]
The enzymes responsible for GSH synthesis, such as glutamate-cysteine ligase modifier subunit (GCLM) and the glutamate-cysteine catalytic subunit (GCLC), and enzymes related to GSH utilization, such as glutathione reductase, glutathione peroxidase and glutathione S transferase (GST), have their transcription regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), known as the master regulator of antioxidant response[16]
The cell sensitivity to cisplatin treatment was evaluated in one normal lung fibroblast cell line (IMR-90) and two non-small-cell lung carcinoma (NSCLC) cell lines (A549 and NCI H23)
Summary
Cancer is one of the main causes of morbidity and mortality worldwide, with a total annual economic costs of approximately US$ 1.16 trillion, and the number of cases are expected to rise 70% over the two decades[1]. MMR removes the base opposite to the adduct, which may cause a new mismatch, starting the pathway again and leading to the so-called futile cycle, generating double stranded breaks This process can inhibit the removal of cisplatin lesions by NER and leading to cell death. Other important resistance mechanisms prevent the drug from reaching the DNA and causing lesions One of these mechanisms is the reduction in the intracellular accumulation of cisplatin due to an increase in the thiol-containing protein-mediated inactivation, such as glutathione (GSH), a highly abundant and low-molecular-weight tripeptide (Glu-Cys-Gly), well known antioxidant in cells. The importance of NRF2 to cisplatin resistance has been demonstrated recently, and its overexpression has been correlated with higher resistance to several chemotherapeutic drugs in different types of cancer[17]
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