The NFκB-mediated control of RS and JNK signaling in vitamin A-treated cells: Duration of JNK–AP-1 pathway activation may determine cell death or proliferation

Abstract

Nuclear factor kappa B (NFκB) has emerged as a crucial regulator of cell survival, playing important functions in cellular resistance to oxidants and chemotherapeutic agents. Recent studies showed that NFκB mediates cell survival through suppression of the accumulation of reactive species (RS) and a control of sustained activation of the Jun-N-terminal kinase (JNK) cascade. This work was undertaken in order to evaluate the role of NFκB in modulating the pro-oxidant effects of supplementation with vitamin A (retinol, ROH) in Sertoli cells, a major ROH physiological target. In this work, we reported that ROH treatment increases mitochondrial RS formation leading to a redox-dependent activation of NFκB. NFκB activation played a pivotal role in counteract RS accumulation in ROH-treated cells, since NFκB inhibition with DNA decoy oligonucleotides or pharmacological inhibitors (BAY-117082) potentiated ROH-induced RS accumulation and oxidative damage. In the presence of NFκB inhibition, ROH-induced oxidative stress promoted a prolonged activation of the JNK–activator protein 1 (AP-1) pathway and induced significant decreases in cell viability. Inhibition of JNK–AP-1 with decoy oligonucleotides to AP-1 or JNK inhibitor SP600125 prevented the decreases in cell viability. Antioxidants blocked the persistent JNK–AP-1 activation, cell oxidative damage, and the decreases in cell viability induced by NFκB inhibition. Finally, our data point superoxide dismutase (SOD)2 as a potential antioxidant factor involved in NFκB protective effects against ROH-induced oxidative stress. Taken together, data presented here show that NFκB mediates cellular resistance to the pro-oxidant effects of vitamin A by inhibiting RS accumulation and the persistent and redox-dependent activation of JNK–AP-1 cascade.