The Expression of TP53-Induced Glycolysis and Apoptosis Regulator (TIGAR) Can Be Controlled by the Antioxidant Orchestrator NRF2 in Human Carcinoma Cells

• Published in: International journal of molecular sciences 2022-02, Vol.23 (3), p.1905
• Main Authors: Simon-Molas, Helga, Sánchez-de-Diego, Cristina, Navarro-Sabaté, Àurea, Castaño, Esther, Ventura, Francesc, Bartrons, Ramon, Manzano, Anna
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins - genetics; Binding sites; Biomedical materials; Cancer therapies; Carcinoma; Cell Line, Tumor; Cervical cancer; Cytoplasm; Dehydrogenases; Enzymes; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genes; Glucosephosphate dehydrogenase; Glucosephosphate Dehydrogenase - genetics; Glycolysis; HCT116 Cells; HeLa Cells; Homeostasis; Humans; Kinases; Metabolism; Mice; Mutation; NAD(P)H Dehydrogenase (Quinone) - genetics; Neoplasms - genetics; Neoplasms - metabolism; NF-E2-Related Factor 2 - metabolism; NRF2 protein; Osteoblasts - cytology; Osteoblasts - metabolism; Oxidative stress; p53 Protein; Pentose; Pentose phosphate pathway; Phosphoric Monoester Hydrolases - genetics; Primary Cell Culture; Promoter Regions, Genetic; Proteins; Regulatory sequences; Transcription; Transcription factors; Tumor cell lines; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031905

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 ( ) is an important regulator of glycolysis and the pentose phosphate pathway that was described as a p53 response gene, yet expression is detected in p53-null tumors. In this study we investigated the role of NRF2 in the regulation of in human carcinoma cell lines. Exposure of carcinoma cells to electrophilic molecules or overexpression of NRF2 significantly increased expression of , in parallel to the known NRF2 target genes and . The same was observed in KO cells, indicating that NRF2-mediated regulation of is p53-independent. Accordingly, downregulation of NRF2 decreased the expression of 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 were described. This study provides the first evidence that NRF2 controls the expression of at the transcriptional level.