PMID- 12438277 OWN - NLM STAT- MEDLINE DCOM- 20021217 LR - 20191210 IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 62 IP - 22 DP - 2002 Nov 15 TI - Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3'-kinase pathway. PG - 6756-63 AB - Neuroblastoma (NB) tumors expressing high levels of brain-derived neurotrophic factor (BDNF) and TrkB are associated with poor 5-year survival outcomes. Our previous studies indicated that BDNF blocked the cytotoxic effects of vinblastine on NB cells. Here we evaluated the ability of BDNF to decrease the chemosensitivity of NB cells to a number of common chemotherapeutic agents. Two SH-SY5Y NB cell lines (TB3 and TB8) expressing TrkB under the control of a tetracycline (Tet)-repressible promoter element were generated, and used to assess apoptosis resulting from treatment with cisplatin, doxorubicin, etoposide, and vinblastine. BDNF treatment of high TrkB-expressing TB8 (Tet-) and TB3 (Tet-) cells blocked drug-induced cell death in a dose-dependent manner. Only high-dose BDNF (100 ng/ml) could block the effects of chemotherapy in low TrkB-expressing cells. The ability of BDNF to rescue the cells from chemotherapeutic agent-induced cell death was inhibited by treatment with the Trk tyrosine kinase inhibitor K252a or the phosphatidylinositol 3'-kinase (PI3K) inhibitor LY294002, but not by the mitogen-activated protein kinase kinase inhibitor PD98059 or the peritoneal lymphocyte gamma inhibitor U73122, indicating that both TrkB and PI3K activities are required for the survival-promoting effects of BDNF. BDNF also protected TrkB-expressing NGP and KCNR NB cells from chemotherapeutic agent-induced cell death, and LY294002 inhibited this protection. These results suggest that TrkB and BDNF can contribute to the chemoresistance of poor prognosis tumors, and that suppression of PI3K activity might improve the ability of these agents to induce the death of NB tumors. FAU - Jaboin, Jerry AU - Jaboin J AD - Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. FAU - Kim, Chong Jai AU - Kim CJ FAU - Kaplan, David R AU - Kaplan DR FAU - Thiele, Carol J AU - Thiele CJ LA - eng PT - Journal Article PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 5V9KLZ54CY (Vinblastine) RN - 6PLQ3CP4P3 (Etoposide) RN - 80168379AG (Doxorubicin) RN - EC 2.7.10.1 (Receptor, trkB) RN - F8VB5M810T (Tetracycline) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Animals MH - Apoptosis/drug effects/physiology MH - Brain-Derived Neurotrophic Factor/metabolism/*pharmacology/physiology MH - Cisplatin/pharmacology MH - Dose-Response Relationship, Drug MH - Doxorubicin/pharmacology MH - Drug Resistance, Neoplasm MH - Enzyme Activation MH - Etoposide/pharmacology MH - Humans MH - Neuroblastoma/drug therapy/*enzymology/pathology MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Phosphoinositide-3 Kinase Inhibitors MH - Promoter Regions, Genetic MH - Rats MH - Receptor, trkB/antagonists & inhibitors/*metabolism MH - Signal Transduction/drug effects/physiology MH - Tetracycline/pharmacology MH - Transfection MH - Tumor Cells, Cultured MH - Vinblastine/pharmacology 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):6756-63.