Excessive oxidative stress has been considered as one of the key factors in development of several neurodegenerative conditions, cancers and cardiovascular diseases. A battery of protective enzymes, such as glutathione S-transferases and NADPH quinone oxidoreductases has evolved in order to combat the excessive oxidative stress. Antioxidant response element (ARE) is a conservative domain found in the promoter region of majority of genes responsible for expression of protective enzymes. The expression of the genes that contain ARE is regulated by the transcription factor NRF2 (NFE2L2) which in turn is regulated by Keap-1 protein.
UPF1 and UPF17 are glutathione (GSH) analogues, developed recently by Ehrlich et al. which outperform free radical scavenging properties of GSH, while not showing any toxicity to the cells [1]. Although similar in structure, UPF1 and UPF17 show diverse effects on the Antioxidant Defense System as shown by Kairane et al. in Human Erythroleukemia Cells K562 with UPF1 increasing the cellular GSH levels, while UPF17 having the opposite effect [2].
In the present study we investigated if the increase and decrease of the cellular GSH levels induced by the UPF peptides are related to the intracellular localization and expression of the ARE activating transcription factor NRF2. We found that while UPF1 and UPF17 have neglible effect on the mRNA expression in human HepG2 cells, the peptides have diverse effects on the intracellular localization of the NRF2. UPF1 increased the NRF2 levels in the nucleus after 15 min incubation with peptide, while UPF17 after 15 min lowered the nuclear NRF2 levels.
Together our data suggests that GSH analogues UPF1 and UPF17 have effect on the activation of ARE when affecting the intracellular localization of it's transcription factor NRF2.