Inhibition of H2O2-induced cell death through FOXO1 modulation by EUK-172 in SK-N-MC cells.

ABSTRACT

It has been suggested that excess accumulation of reactive oxygen species, termed oxidative stress, may lead to neuronal death resulting in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. In oxidative stress-induced cell death numerous transcription factors are thought to be involved. One of them is Forkhead box protein O1 (FOXO1) that governs many genes involved in oxidative stress resistance, DNA repair, cell cycle arrest, proliferation and apoptosis. Apparently, FOXO1 activity is tightly linked to post translational modifications including phosphorylation and acetylation, which are modulated by many factors such as oxidative stress. Reactive oxygen species, as the major players in oxidative stress, guide FOXO1 nuclear localization at least by simultaneous c-Jun N-terminal kinase (JNK) activation and Akt/PKB activity suppression. Here, we showed that a synthetic salen-manganese derivative (EUK-172) with strong catalase activity reduced oxidative stress evident through marked reduction in intracellular reactive oxygen species, protein carbonylation and lipid peroxidation. In addition, our results indicated that EUK-172 not only reduced the FOXO1 protein content, but also it inhibited FOXO1 nuclear translocation in H(2)O(2)-exposed SK-N-MC cells. These events attenuated caspase-3 activity and bax/Bcl-2 ratio leading to higher viability of the H(2)O(2)-treated SK-N-MC cells.