Induction of CYP1 Family Members under Low-glucose Conditions Requires AhR Expression and Occurs through the Nuclear Translocation of AhR

Cross-talk between the aryl hydrocarbon receptor (AhR) pathway and the typical stress response is thought to be an important signal transduction in response to nutrient-stress conditions, such as glucose deprivation in liver cells. In the present study, we demonstrate that reduction of glucose concentration in the medium of HepG2 cells, a human hepatocellular carcinoma cell line, induces the CYP1 family and Nrf2. RNAi for AhR abolishes the induction of expression of CYP1 and Nrf2. These inductions are accompanied by the translocation of AhR into the nucleus in response to low-glucose conditions. Endogenous compounds are recruited as AhR ligands to induce various gene expressions, and our present results suggest that an endogenous AhR ligand is produced under low-glucose conditions and that the role of AhR as a transcription factor is related to the low-glucose response. The recommended glucose concentration (4.5g/L) in the medium for culture of HepG2 was used as the high-glucose concentration in this study. We adopted 1.0g/L as the low-glucose condition for elucidation of mechanisms of the stress response. These results will be useful to understand the relationship between drug-metabolizing enzymes and mechanisms of the anti-stress response of tumor cells, and will also be useful for investigating preventive remedies against tumor angiogenesis.