0

Neurotrophin-3 Production Promotes Human Neuroblastoma Cell Survival by Inhibiting TrkC-induced Apoptosis

Jimena Bouzas-Rodriguez, Jorge Ruben Cabrera, Céline Delloye-Bourgeois, Gabriel Ichim, Jean-Guy Delcros, Marie-Anne Raquin, Raphaël Rousseau, Valérie Combaret, Jean Bénard, Servane Tauszig-Delamasure, Patrick Mehlen

J Clin Invest. 2010 Mar;120(3):850-8.

PMID: 20160348

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.

Chemicals Related in the Paper:

Catalog Number Product Name Structure CAS Number Price
IAR4248624 Neurotrophin-3 human Neurotrophin-3 human Price
qrcode