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

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.

Role of Glutathione in Cancer: From Mechanisms to Therapies

“…Indeed the upregulation of NRF2 (nuclear factor, erythroid-derived 2-like 2 factor) has been observed in a wide array of tumors including breast, ovarian, prostate, skin, lung and pancreas [ 32 , 44 ]. NRF2 is a master regulator of antioxidant response as a transcription factor regulating expression of several enzymes responsible for glutathione synthesis, including glutamate-cysteine ligase modifier subunit (GCLM) and the glutamate-cysteine catalytic subunit (GCLC), as well as enzymes related to GSH utilization, such as glutathione reductase, glutathione peroxidase and glutathione S transferase (GST) [ 45 , 46 ].…”

ROS-Mediated Therapeutic Strategy in Chemo-/Radiotherapy of Head and Neck Cancer

“…Increased GSH has long been considered as an accomplice in the progression and multidrug resistance of cancer [122][123][124][125][126]. GSH depletion obtained by the irreversible GCL inhibitor BSO is the most commonly used method and is associated with many chemotherapy drugs.…”

The Impact of Diet on the Involvement of Non-Coding RNAs, Extracellular Vesicles, and Gut Microbiome-Virome in Colorectal Cancer Initiation and Progression

“…The expression of several genes is activated by these factors: and thus, influencing immune responses, growth factors, and cell cycle transition. Nrf2 regulates the transcription of glutathione peroxidase and glutathione S-transferase (GST), glutathione reductase, glutamate-cysteine catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM) ( 172 ). Contrarily, the modification of cysteine residues on KEAP1 occur under oxidative stress, this alters and disrupt the association of KEAP1 with Nrf2, thereby stabilizing Nrf2 ( 39 ).…”