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

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.
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Submitted on : Wednesday, April 21, 2010 - 4:04:06 PM
Last modification on : Tuesday, November 19, 2019 - 2:39:08 AM
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Jimena Bouzas-Rodriguez, Jorge Ruben Cabrera, Céline Delloye-Bourgeois, Gabriel Ichim, Jean-Guy Delcros, et al.. Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis.. Journal of Clinical Investigation, American Society for Clinical Investigation, 2010, 120 (3), pp.850-8. ⟨10.1172/JCI41013⟩. ⟨hal-00475272⟩

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