Papel da ativação do fator de transcrição NRF2 na diferenciação de células SH-SY5Y mediada por Ácido Retinóico

Abstract

Retinoic acid (RA) morphogenetic properties has been used in different kinds of therapies, from neurodegenerative disorders to some types of cancer such as promyelocytic leukaemia and neuroblastoma. However, most of the pathways responsible for RA effects remain unknown. To investigate such pathways, we used a RA-induced differentiation model in the human neuroblastoma cells, SH-SY5Y. Our data showed that n-acetyl-cysteine (NAC) reduced cells proliferation rate and increased cells sensitivity to RA toxicity. Simultaneously, NAC pre-incubation attenuated NRF2 activation by RA. None of these effects were obtained with Trolox® as antioxidant, suggesting a cysteine signalization by RA. NRF2 knockdown increased cell sensibility to RA after 96 h of treatment and diminished neuroblastoma proliferation rate. Conversely, NRF2 overexpression limited RA anti-proliferative effects and increased cell proliferation. In addition, a rapid and non-genomic activation of ERK 1/2 and PI3K/AKT pathway revealed to be equally required to promote NRF2 activation and necessary to RA-induced differentiation. Together, we provide data correlating NRF2 activity with neuroblastoma proliferation and resistance to RA treatments, thus this pathway could be a potential target to optimize neuroblastoma chemotherapeutic response as well as in vitro neuronal differentiation protocols.