title: TrkA induces apoptosis of neuroblastoma cells and does so via a p53-dependent mechanism.
abstract: Neuroblastoma (NB) is the most frequent solid extracranial tumor in children. Its clinical prognosis correlates with the expression of members of the Trk neurotrophin receptor family, which includes TrkA and TrkB. TrkA expression is associated with favorable prognosis, whereas TrkB expression is associated with poor prognosis. Here we show that TrkA expression induces the apoptosis of NB cells and does so by modulating the levels or activities of a number of proteins involved in regulating cell survival and apoptosis, including p53, Bcl-2, and caspase-3. TrkA increased the expression of p53 target proteins and failed to induce apoptosis in cells where p53 was inactivated by mutation or via expression of dominant inhibitory p53 or E1B55K, indicating that TrkA mediates apoptosis, at least in part, through p53. Treatment with a caspase inhibitor or overexpression of Bcl-X(L) also prevented TrkA from inducing apoptosis. In contrast, elevated expression of TrkA in non-transformed sympathetic neurons resulted in the suppression of p53 levels and enhanced survival. These results identify apoptosis as a novel biological response of TrkA in NB cells and imply that TrkA is a good prognosis marker for NB due in part to its ability to mediate apoptosis when expressed at sufficient levels.
authors.affiliation: Cancer Research Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lavoie
authors.forename: Lynne
authors.initials: L
authors.lastname: Lesauteur
authors.forename: Judi
authors.initials: J
authors.lastname: Kohn
authors.forename: Josee
authors.initials: J
authors.lastname: Wong
authors.forename: Olivia
authors.initials: O
authors.lastname: Furtoss
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Thiele
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D015153:Blotting, Western; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation; D009447:Neuroblastoma / Q000473:pathology*; D009474:Neurons / Q000378:metabolism; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020917:Receptor, trkA / Q000378:metabolism / Q000502:physiology*; D020813:Receptor, trkB / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; D061945:Caspase Inhibitors; D004396:Coloring Agents; D004791:Enzyme Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D020917:Receptor, trkA; D020813:Receptor, trkB; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C022616:thiazolyl blue