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Chemoresistance and increased tumor expression of TrkB and Brain-derived neurotrophic factor (BDNF) are two biomarkers of poor prognosis in neuroblastoma (NB) patients. Understanding the signal transduction pathways that affect the sensitivity of NB cells to chemotherapy is important for developing more effective therapies. Previously we found that BDNF activation of TrkB through PI3K/Akt protects NB from etoposide/cisplatin induced cell death. Bim, a BH3-only member of death activators in the Bcl-2 superfamily, modulates the intrinsic mitochondrial death pathway and is regulated by multiple growth factor signaling pathways. In this study we investigated the role of Bim in the brain-derived neurotrophic factor (BDNF)/TrkB protection of NB cells from chemotherapy-induced cell death. The three chemotherapeutic drugs paclitaxel, etoposide and cisplatin were used in this study to investigate the role of Bim in the brain-derived neurotrophic factor (BDNF)/TrkB protection of NB cells from chemotherapy-induced cell death. Gene silencing experiments showed that silencing of Bim with siRNA protected the NB cells from paclitaxel but not etoposide or cisplatin-induced cell death. Using pharmacological and genetic methods, we found that BDNF-induced reduction of Bim was regulated by the MAPK pathway, but not by the PI3K/Akt pathway. Both MAPK and PI3K pathways were involved in the BDNF protection of NB cells from paclitaxel-induced cell death, while PI3K pathway only was involved in BDNF protection of NB cells from etoposide or cisplatin-induced cell death. Thus the role of Bim in BDNF protection of NB cells from chemotherapy depended on the chemotherapeutic drugs used. These data indicate that different chemotherapeutic drugs induce distinct death pathways and that growth factors utilize different signal transduction pathways to modulate the effects of chemotherapy on cells.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]