Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis.
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.
Bouzas-Rodriguez
Jimena
J
Apoptosis, Cancer and Development Laboratory-Equipe labellisée "La Ligue," CNRS UMR, Université de Lyon, France.
Cabrera
Jorge Ruben
JR
Delloye-Bourgeois
Céline
C
Ichim
Gabriel
G
Delcros
Jean-Guy
JG
Raquin
Marie-Anne
MA
Rousseau
Raphaël
R
Combaret
Valérie
V
Bénard
Jean
J
Tauszig-Delamasure
Servane
S
Mehlen
Patrick
P
D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D002470:Cell Survival; D002645:Chickens; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D020933:Neurotrophin 3 / Q000096:biosynthesis* / Q000235:genetics; D020812:Receptor, trkC / Q000096:biosynthesis* / Q000235:genetics; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000235:genetics
D009363:Neoplasm Proteins; D020933:Neurotrophin 3; D020812:Receptor, trkC