Influence of Melatonin Treatment on Cellular Mechanisms of Redox Adaptation in K562 Erythroleukemic Cells

Abstract

Melatonin (MEL) presents well-documented pleiotropic actions against oxidative stress (OS), acting indirectly through activation of transcription factors, e.g., FoxO3 and Nrf2. Thus, this study aimed to investigate the possible modulating effects of MEL on the redox signaling pathways PI3K/AKT/FoxO3 and Keap1/Nrf2/ARE in K562 erythroleukemic cells subjected to OS induction. For this, the viability, and transcript levels of genes involved in redox adaptation were evaluated in K562 cells in different periods of erythroid differentiation: under OS induction by hydrogen peroxide (100 µM H2O2); treated with 1 nM (C1) and 1 mM (C2) MEL; and associated or not with stress induction. We observed a restoration of physiological levels of Nrf2 in both MEL concentrations under OS. The C1 was related to enhanced expression of antioxidant and proteasome genes through the Nrf2-ARE pathway, while C2 to the induction of FOXO3 expression, suggesting an involvement with apoptotic pathway, according to BIM transcript levels. The effects of MEL administration in these cells showed a period and dose-dependent pattern against induced-OS, with direct and indirect actions through different pathways of cellular adaptation, reinforcing the importance of this indolamine in the regulation of cellular homeostasis, being a promising therapeutic alternative for diseases that present an exacerbated OS.

Agomelatine, a Melatonin-Derived Drug, as a New Strategy for the Treatment of Colorectal Cancer

“…Further research is warranted to determine the mechanism underlying these differences. The antioxidant ability of melatonin is extended to the regulation of the expression and activity of PRX1 [ 55 ], although there are no available data regarding the role of p53 in this action of the indoleamine.…”

Melatonin: A Potential Regulator of DNA Methylation

“…Under physiological conditions, Nrf2 is ubiquitinated via ligase E3 complex Keap1-Cul3-Rbx1, which is followed by its proteasomal degradation. However, under oxidative stress, Nrf2 degradation is suppressed, allowing for its translocation to the nucleus and binding to antioxidant response element 2 (ARE) [ 28 , 29 ], which is located in the regulatory regions of genes encoding numerous antioxidant enzymes, including superoxide dismutase (Mn-SOD, Cu/Zn-SOD), catalase (CAT), γ -glutamylcysteine synthetase ( γ -GCS), heme oxygenase-1 (HO-1), NADPH quinone dehydrogenase-1 (NQO1), or glutathione peroxidase (GPx) [ 4 , 19 , 30 , 31 , 32 , 33 ]. Apart from this, melatonin affects Nrf2 via the inhibition of degradation and the promotion of its nuclear translocation [ 29 , 31 , 34 ].…”

“…Apart from this, melatonin affects Nrf2 via the inhibition of degradation and the promotion of its nuclear translocation [ 29 , 31 , 34 ]. Moreover, a recent in vitro study revealed that 1 nM melatonin can effectively stimulate Nrf2 via an increase in the expression levels of antioxidant and proteasome genes linked with the Keap1-Nrf2-ARE pathway [ 28 ].…”