Abstract
Chemoresistance and increased expression of TrkB and brain-derived neurotrophic factor (BDNF) are biomarkers of poor prognosis in tumors from patients with neuroblastoma (NB). Previously, we found BDNF activation of TrkB through PI3K/Akt protects NB from etoposide/cisplatin-induced cell death. In this study, the role of Bim, a proapoptotic protein, was investigated. Bim was involved in paclitaxel but not etoposide or cisplatin-induced cell death in NB cells. Pharmacological and genetic studies showed that BDNF-induced decreases in Bim were regulated by MAPK and not PI3K/Akt pathway. Both MAPK and PI3K pathways were involved in BDNF protection of NB cells from paclitaxel-induced cell death, while PI3K predominantly mediated BDNF protection of NB cells from etoposide or cisplatin-induced cell death. These data indicate that different chemotherapeutic drugs induce distinct death pathways and growth factors utilize different signal transduction pathways to modulate the effects of chemotherapy on cells.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Bcl-2-Like Protein 11
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Brain-Derived Neurotrophic Factor / pharmacology*
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Cell Death / drug effects
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Cisplatin / pharmacology
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Down-Regulation / drug effects*
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Enzyme Activation / drug effects
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Etoposide / pharmacology
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Forkhead Box Protein O3
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Forkhead Transcription Factors / metabolism
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Silencing
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mitogen-Activated Protein Kinases / metabolism
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Molecular Mimicry / drug effects
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Neuroblastoma / enzymology*
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Neuroblastoma / genetics
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Neuroblastoma / pathology*
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Paclitaxel / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Receptor, trkB / genetics
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Receptor, trkB / metabolism*
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Brain-Derived Neurotrophic Factor
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FOXO3 protein, human
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Membrane Proteins
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Protein Isoforms
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Proto-Oncogene Proteins
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RNA, Messenger
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RNA, Small Interfering
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Etoposide
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Phosphatidylinositol 3-Kinases
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Receptor, trkB
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Mitogen-Activated Protein Kinases
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Paclitaxel
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Cisplatin