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

Bouzas-Rodriguez, J. et al. (2010) Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis. Journal of Clinical Investigation, 120(3), pp. 850-858. (doi: 10.1172/JCI41013)

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Publisher's URL: http://dx.doi.org/10.1172/JCI41013

Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ichim, Dr Gabriel
Authors: Bouzas-Rodriguez, J., Cabrera, J. R., Delloye-Bourgeois, C., Ichim, G., Delcros, J.-G., Raquin, M.-A., Rousseau, R., Combaret, V., Bénard, J., Tauszig-Delamasure, S., and Mehlen, P.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Journal of Clinical Investigation
Publisher:Americal Society for Clinical Investigation
ISSN:0021-9738
ISSN (Online):1558-8238

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