PMID- 12438236
OWN - NLM
STAT- MEDLINE
DCOM- 20021217
LR  - 20220310
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 62
IP  - 22
DP  - 2002 Nov 15
TI  - Resistance to chemotherapy mediated by TrkB in neuroblastomas.
PG  - 6462-6
AB  - Neuroblastoma is a common childhood tumor derived from the peripheral nervous 
      system. Favorable neuroblastomas usually express TrkA, the receptor for nerve 
      growth factor (NGF), whereas unfavorable, MYCN-amplified neuroblastomas usually 
      express TrkB and its ligand, brain-derived neurotrophic factor (BDNF). Here, we 
      provide evidence that the TrkB-BDNF pathway is associated with enhanced survival 
      and resistance to chemotherapy in neuroblastoma. We transfected the neuroblastoma 
      line SH-SY5Y, which has endogenous expression of BDNF, with a full-length TrkB 
      expression vector, and obtained clones with moderate or high levels of 
      expression. Cells were exposed in vitro to chemotherapy agents used to treat 
      neuroblastomas: doxorubicin, etoposide (VP16), and cisplatin. Chemoresistance was 
      measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) 
      assay for cell survival and by ELISA for cell death. In all cases, the 
      TrkB-expressing subclones were more resistant to treatment than the parent line. 
      Furthermore, when the TrkB tyrosine kinase was blocked with the Trk-specific 
      inhibitor CEP-2563, or by neutralizing antibody to BDNF, sensitivity to 
      chemotherapy was significantly increased. We also found constitutive 
      phosphorylation of AKT at the Ser-473 site in TrkB transfectants, whereas there 
      was only a minimal level of constitutive phosphorylation of AKT in SY5Y cells. 
      These results show that the TrkB-BDNF pathway provides a survival advantage when 
      exposed to DNA-damaging reagents, and, therefore, this autocrine pathway may play 
      an important role in mediating the drug-resistant phenotype associated with 
      TrkB-expressing neuroblastomas. Activation of PI3K/AKT survival pathway may 
      contribute to the increased drug resistance in TrkB-expressing neuroblastomas.
FAU - Ho, Ruth
AU  - Ho R
AD  - Division of Oncology, the Children's Hospital of Philadelphia and the University 
      of Pennsylvania, Philadelphia, Pennsylvania 19104-4318, USA.
FAU - Eggert, Angelika
AU  - Eggert A
FAU - Hishiki, Tomoro
AU  - Hishiki T
FAU - Minturn, Jane E
AU  - Minturn JE
FAU - Ikegaki, Naohiko
AU  - Ikegaki N
FAU - Foster, Patricia
AU  - Foster P
FAU - Camoratto, Anna Marie
AU  - Camoratto AM
FAU - Evans, Audrey E
AU  - Evans AE
FAU - Brodeur, Garrett M
AU  - Brodeur GM
LA  - eng
GR  - CA-94194/CA/NCI NIH HHS/United States
GR  - NS-34514/NS/NINDS NIH HHS/United States
GR  - T32-CA09615/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antibodies)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Enzyme Inhibitors)
RN  - 6PLQ3CP4P3 (Etoposide)
RN  - 80168379AG (Doxorubicin)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Antibodies/pharmacology
MH  - Apoptosis/drug effects/physiology
MH  - Brain-Derived Neurotrophic Factor/antagonists & 
      inhibitors/biosynthesis/genetics/immunology
MH  - Cisplatin/pharmacology
MH  - Doxorubicin/pharmacology
MH  - Drug Resistance, Multiple/*physiology
MH  - Drug Resistance, Neoplasm
MH  - Enzyme Inhibitors/pharmacology
MH  - Etoposide/pharmacology
MH  - Humans
MH  - Neuroblastoma/*drug therapy/genetics/metabolism
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors
MH  - Receptor, trkB/genetics/metabolism/*physiology
MH  - Transfection
MH  - Tumor Cells, Cultured
EDAT- 2002/11/20 04:00
MHDA- 2002/12/18 04:00
CRDT- 2002/11/20 04:00
PHST- 2002/11/20 04:00 [pubmed]
PHST- 2002/12/18 04:00 [medline]
PHST- 2002/11/20 04:00 [entrez]
PST - ppublish
SO  - Cancer Res. 2002 Nov 15;62(22):6462-6.