Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
NRF2 is a transcription factor that responds to electrophiles and reactive oxygen species. NRF2 activity is precisely regulated through KEAP1 harboring multiple reactive cysteine residues. NRF2 inducers form cysteine adducts to Keap1 protein. Electrophilic Nrf2 inducers including botanical ingredients and environmental chemicals directly bind to cysteine residues in KEAP1 resulting the NRF2 activation, which regulates expression of cytoprotective genes, such as those for antioxidants and detoxication enzymes. Food-contaminated mycotoxin Aflatoxin B1 (AFB1) is a causative chemical of liver cancers. AFB1 metabolite forms DNA adducts, leading to gene mutations. As NRF2 inducers upregulate enzymes responsible for AFB1 detoxication, they exert hepatoprotective effects. Constitutive activation of NRF2 has been found in various types of cancers with relatively high frequency due to somatic gene mutations in NRF2 or KEAP1 genes. Those NRF2-addicted cancers acquire antioxidant and proliferative capacity. Cisplatin is an anti-cancer drug that forms adducts to DNA, leading to cell death. Occasionally, cisplatin-resistant cancers arise and specific treatments toward the resistant cancers need to be explored. In our attempt to generate cisplatin-resistant cancer cell lines, we found that some of the cisplatin-resistant cell lines become NRF2-addicted cancers. Our hypotheses as to how those cell lines acquire NRF2 activation upon exposure to cisplatin will be discussed based on multiple standpoints, in special reference to the DNA adduct formation.
