Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis
Open Access
- 1 March 2010
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 120 (3), 850-858
- https://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.Keywords
This publication has 53 references indexed in Scilit:
- Netrin-1 acts as a survival factor for aggressive neuroblastomaThe Journal of Experimental Medicine, 2009
- EphrinB3 is an anti-apoptotic ligand that inhibits the dependence receptor functions of EphA4 receptors during adult neurogenesisBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2009
- Interference With Netrin-1 and Tumor Cell Death in Non–Small Cell Lung CancerJNCI Journal of the National Cancer Institute, 2009
- Netrin-1 is a survival factor during commissural neuron navigationProceedings of the National Academy of Sciences of the United States of America, 2008
- Making the Case for DCC and UNC5C as Tumor-Suppressor Genes in the ColonGastroenterology, 2007
- Inactivation of the UNC5C Netrin-1 Receptor Is Associated With Tumor Progression in Colorectal MalignanciesGastroenterology, 2007
- The TrkC receptor induces apoptosis when the dependence receptor notion meets the neurotrophin paradigmProceedings of the National Academy of Sciences of the United States of America, 2007
- Anaplastic Lymphoma Kinase Is a Dependence Receptor Whose Proapoptotic Functions Are Activated by Caspase CleavageMolecular and Cellular Biology, 2006
- RGM and its receptor neogenin regulate neuronal survivalNature, 2004
- Gene expression of TrkC (NTRK3) in human soft tissue tumoursThe Journal of Pathology, 2002