Abstract
Hyperactivation of the KEAP1-NRF2 axis is a common molecular trait in carcinomas from different origin. The transcriptional program induced by NRF2 involves antioxidant and metabolic genes that render cancer cells more capable of dealing with oxidative stress. The TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) is an important regulator of glycolysis and the pentose phosphate pathway that was described as a p53 response gene, yet TIGAR expression is detected in p53-null tumors. In this study we investigated the role of NRF2 in the regulation of TIGAR in human carcinoma cell lines. Exposure of carcinoma cells to electrophilic molecules or overexpression of NRF2 significantly increased expression of TIGAR, in parallel to the known NRF2 target genes NQO1 and G6PD. The same was observed in TP53KO cells, indicating that NRF2-mediated regulation of TIGAR is p53-independent. Accordingly, downregulation of NRF2 decreased the expression of TIGAR in carcinoma cell lines from different origin. As NRF2 is essential in the bone, we used mouse primary osteoblasts to corroborate our findings. The antioxidant response elements for NRF2 binding to the promoter of human and mouse TIGAR were described. This study provides the first evidence that NRF2 controls the expression of TIGAR at the transcriptional level.
Highlights
Introduction iationsThe maintenance of reactive oxygen species (ROS) homeostasis is a critical determinant of cell survival
Activation of the endogenous nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway can be triggered by electrophilic molecules that modify cysteine residues in Kelch-like ECH-associated protein 1 (KEAP1) and allow NRF2 to translocate to the nucleus [29]
KEAP1-NRF2 axis was evaluated at the transcriptional level. Both NRF2 inducers increased the expression of NFE2L2, TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) and the NRF2 target genes glucose-6-phosphate dehydrogenase (G6PD) and NAD(P)H quinone dehydrogenase 1 (NQO1), with SFN
Summary
The maintenance of reactive oxygen species (ROS) homeostasis is a critical determinant of cell survival. A decreased supply of oxygen and nutrients and deregulated metabolic pathways usually pose a threat to the redox balance [1]. An increasing body of evidence indicates that cancer cells adapt to an imbalanced redox status by developing alternative metabolic reactions or by strengthening existing ones. This allows them to balance ROS according to their needs and renders them insensitive to further stress inducers such as chemotherapy and radiation [1].
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