Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis

Tropomyosin-related kinase receptor C (TrkC) is a neurotrophin receptor with tyrosine kinase activity that was expected to be oncogenic. However, it has several characteristics of a tumor suppressor: its expression in tumors has often been associated with good prognosis; and it was recently demonstr...

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Bibliographic Details
Published in:The Journal of clinical investigation 2010-03, Vol.120 (3), p.850-858
Main Authors: Bouzas-Rodriguez, Jimena, Cabrera, Jorge Ruben, Delloye-Bourgeois, Céline, Ichim, Gabriel, Delcros, Jean-Guy, Raquin, Marie-Anne, Rousseau, Raphaël, Combaret, Valérie, Bénard, Jean, Tauszig-Delamasure, Servane, Mehlen, Patrick
Format: Article
Language:English
Subjects:
Animals
Antibodies
Apoptosis
Autocrine Communication
Biochemistry, Molecular Biology
Biomedical research
Cancer therapies
Care and treatment
Cell death
Cell Line, Tumor
Cell Survival
Chickens
Gene amplification
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Genetic aspects
Health aspects
Humans
Kinases
Life Sciences
Ligands
Medical prognosis
Mice
Mice, Nude
Molecular biology
Neoplasm Proteins
Neoplasm Proteins - biosynthesis
Neoplasm Proteins - genetics
Neoplasm Transplantation
Nervous system
Neuroblastoma
Neuroblastoma - genetics
Neuroblastoma - metabolism
Neuroblastoma - pathology
Neuroblastoma - therapy
Neurotrophic functions
Neurotrophin 3
Neurotrophin 3 - biosynthesis
Neurotrophin 3 - genetics
Physiological aspects
Receptor, trkC
Receptor, trkC - biosynthesis
Receptor, trkC - genetics
Risk factors
Transplantation, Heterologous
Tumors
Up-Regulation
Up-Regulation - genetics
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Summary:Tropomyosin-related kinase receptor C (TrkC) is a neurotrophin receptor with tyrosine kinase activity that was expected to be oncogenic. However, it has several characteristics of a tumor suppressor: its expression in tumors has often been associated with good prognosis; and it was recently demonstrated to be a dependence receptor, transducing different positive signals in the presence of ligand but inducing apoptosis in the absence of ligand. Here we show that the TrkC ligand neurotrophin-3 (NT-3) is upregulated in a large fraction of aggressive human neuroblastomas (NBs) and that it blocks TrkC-induced apoptosis of human NB cell lines, consistent with the idea that TrkC is a dependence receptor. Functionally, both siRNA knockdown of NT-3 expression and incubation with a TrkC-specific blocking antibody triggered apoptosis in human NB cell lines. Importantly, disruption of the NT-3 autocrine loop in malignant human neuroblasts triggered in vitro NB cell death and inhibited tumor growth and metastasis in both a chick and a mouse xenograft model. Thus, we believe that our data suggest that NT-3/TrkC disruption is a putative alternative targeted therapeutic strategy for the treatment of NB.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci41013