Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas.
Elevated expression of the neurotrophin-3 (NT-3) receptor TrkC by childhood medulloblastomas is associated with favorable clinical outcome. Here, we provide evidence that TrkC is more than simply a passive marker of prognosis. We demonstrate that: (a) medulloblastomas undergo apoptosis in vitro when grown in the presence of NT-3; (b) overexpression of TrkC inhibits the growth of intracerebral xenografts of a medulloblastoma cell line in nude mice; and (c) trkC expression by individual tumor cells is highly correlated with apoptosis within primary medulloblastoma biopsy specimens. TrkC-mediated NT-3 signaling promotes apoptosis by activating multiple parallel signaling pathways and by inducing immediate-early gene expression of both c-jun and c-fos. Considered collectively, these results support the conclusion that the biological actions of TrkC activation affect medulloblastoma outcome by inhibiting tumor growth through the promotion of apoptosis.
Kim
J Y
JY
Department of Neurology, Children's Hospital, Boston, Massachusetts 02115, USA.
Sutton
M E
ME
Lu
D J
DJ
Cho
T A
TA
Goumnerova
L C
LC
Goritchenko
L
L
Kaufman
J R
JR
Lam
K K
KK
Billet
A L
AL
Tarbell
N J
NJ
Wu
J
J
Allen
J C
JC
Stiles
C D
CD
Segal
R A
RA
Pomeroy
S L
SL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002675:Child, Preschool; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008819:Mice, Nude; D009414:Nerve Growth Factors / Q000494:pharmacology; D020933:Neurotrophin 3; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured