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

• 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
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci41013

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.