TRAIL-related neurotoxicity implies interaction with the Wnt pathway in human neuronal cells in vitro.
Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is involved in amyloid beta dependent neurotoxicity via the extrinsic pathway. Recently, several genes modulating TRAIL cytotoxicity have been characterized, providing evidence for a role of wingless-type mouse mammary tumor virus integration site family (Wnt), Jun-N-terminal kinase and other pathways in increased cell susceptibility to the cytokine. We investigated whether neurotoxic effects of TRAIL could be due to modulation of the Wnt signaling pathway. Western blot analysis of Wnt in SH-SY5Y human neuroblastoma cells showed significantly decreased Wnt expression in cultures treated with TRAIL. Correspondingly, both phosphorylation of glycogen synthase kinase 3 beta and degradation of cytoplasmic beta-catenin were increased, as well as phosphorylation of the tau protein, bringing about the picture of neuronal damage. As a counterproof of the interaction of TRAIL with the Wnt pathway, the addition of the specific glycogen synthase kinase 3 beta inhibitor SB216763 resulted in rescue of a significant percent of cells from TRAIL-induced apoptosis. The rescue was total when the caspase 8 inhibitor z-IETD-FMK was added in combination with SB216763. Results show that, probably, in addition to triggering caspase signaling, TRAIL also interferes with the Wnt pathway, additionally concurring to neuronal damage. These data suggest that the Wnt pathway substantially contributes to the TRAIL-related neurotoxicity and indicate the TRAIL system as a candidate target for pharmacological treatment of Alzheimer's disease and related disorders.
Cantarella
Giuseppina
G
Department of Experimental and Clinical Pharmacology, University of Catania School of Medicine, Catania, Italy.
Di Benedetto
Giulia
G
Pezzino
Salvatore
S
Risuglia
Nunziata
N
Bernardini
Renato
R
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000633:toxicity*; D051153:Wnt Proteins / Q000378:metabolism* / Q000502:physiology
D053221:TNF-Related Apoptosis-Inducing Ligand; D051153:Wnt Proteins