Tumor necrosis factor‐related apoptosis‐inducing ligand reduces the expression of the neuroprotective Na+/Ca2+ exchanger isoform NCX3 in human neuroblastoma SH‐SY5Y cells.

Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), a cytokine belonging to the TNF superfamily, is regarded as a mediator of neurotoxicity. The constitutively expressed ion exchanger Na+/Ca2+ exchanger isoform‐3 (NCX3) has been shown to protect neurons from injury. Its expression is induced by nerve growth factor (NGF) through activation of its tyrosine kinase receptor trkA. The latter, in turn, activates downstream kinases, such as extracellular signal‐regulated kinase (ERK) and the survival‐related kinase protein kinase B (AKT). Here, we verified whether TRAIL could influence the expression of NCX3 via modulation of the NGF/trkA system. Differentiated human neuroblastoma SH‐SY5Y cells were incubated with TRAIL and, subsequently, the expression of the NCX3 protein was studied at different times by means of western blot analysis. Then, the expression of the phosphorylated forms of either trkA, ERK or AKT was analyzed at identical intervals. Western blot analysis revealed that the expression of NCX3 protein decreased in a time‐dependent fashion in SH‐SY5Y cells treated with TRAIL, to reach its minimum at 48 h. On the other hand, p‐trkA, p‐ERK, and p‐AKT expression was increased in cells treated with TRAIL after 6 and 16 h; then it declined to nearly undetectable levels after 48 h. Results indicate that the increase in TRAIL expression occurring during neuronal damage may be responsible of NCX3 down‐regulation and weakens its neuroprotective effects. The TRAIL system could thus represent a potential target for treatment of neuronal damage characterized by NCX3 function impairment. The potent neurotoxic cytokine tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) modulates an array of intracellular pathways, including the cell survival‐related PI3K/protein kinase B (AKT) signaling. The neurotrophin nerve growth factor (NGF) induces up‐regulated expression of the neuroprotective Na+/Ca2+‐exchanger isoform‐3 (NCX3), via PI3K/AKT pathway. Increased expression of TRAIL occurring in neurodegeneration may represent a hurdle to beneficial effects of NGF on neurons, also via down‐regulation of NCX3 and inhibition of AKT phosphorylation. [ABSTRACT FROM AUTHOR]