Ref ID: 356.1

Akt Pathway Mediates BDNF/TrkB Resistance to Chemotherapy in Neuroblastoma cells

Zhijie Li, Jerry Jaboin, Carol J Thiele 

Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.

Patients whose neuroblastoma (NB) tumors expressing high levels of brain-derived neurotrophic factor (BDNF) and TrkB often associated with poor progress. Our previous studies indicated that BDNF blocked the cytotoxic effects of chemotherapeutic drugs such as Etoposide, Vinblastin, Doxorubisin and Cisplatin via phosphatidylinositol 3-kinase(PI3) kinase pathway. Akt, an important downstream target of PI3K, exerts its functions such as regulation of cell cycle, protein synthesis and apoptosis through its downstream targets. In the present study, we examined whether Akt is required and sufficient to mediate BDNF protection of NB cells from chemotherapy. BDNF caused a rapid and time-dependent phosphorylation of Akt, as well as Akt downstream targets p70S6kinase and GSK-3, and these events were inhibited by LY294002, a PI3K inhibitor. Transient transfection of a constitutively-active Akt( Myr-Akt) into the TrkB expressing SY5Y cells TB8 increased total and phosphorylated Akt and attenuated the cell death induced by Etoposide in the absence of BDNF. Furthermore expression of a dominantly-negative Akt blocked the BDNF rescue of NB cells from Etoposide-induced cell death. Besides, Forkhead family members may be the downstream targets of Akt that mediates BDNF rescue of cell death. These results indicated that Akt is a key signaling component by which BDNF protects NB cells from Etoposide-induced cell death. Novel pharmacologic inhibitors targeted to Akt are being evaluated to specifically block the effects of the BDNF/TrkB path and restore the sensitivity of NB cells to chemotherapy.

Presentation mode(s): oral-presentation