This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, Z. Articles by Thiele, C. J. Search for Related Content PubMed PubMed Citation Articles by Li, Z. Articles by Thiele, C. J.

Genetic and Pharmacologic Identification of Akt as a Mediator of Brain-Derived Neurotrophic Factor/TrkB Rescue of Neuroblastoma Cells from Chemotherapy-Induced Cell Death

¹ Cell and Molecular Biology Section, Pediatric Oncology Branch and ² Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and ³ The Second Affiliated Hospital of China Medical University, Shenyang, China

Requests for reprints: Carol J. Thiele, Cell and Molecular Biology Section, Pediatric Oncology Branch, National Cancer Institute, NIH, 10 Center Drive, MSC-1928, Building 10, CRC 1-3940, Bethesda, MD 20892. Phone: 301-496-1543; Fax: 301-451-7052; E-mail: ct47a{at}nih.gov.

Patients whose neuroblastoma tumors express high levels of brain-derived neurotrophic factor (BDNF) and TrkB have an unfavorable prognosis. Our previous studies indicated that BDNF activation of the TrkB signal transduction pathway blocked the cytotoxic effects of chemotherapeutic drugs via the phosphatidylinositol 3-kinase pathway. Akt is an important downstream target of phosphatidylinositol 3-kinase and functions to regulate cell survival, proliferation, and protein synthesis. In this study, we examined whether Akt is required and sufficient to mediate BDNF/TrkB protection of neuroblastoma cells from chemotherapy. Transient transfection of a constitutively active Akt (Akt-Myr) into TrkB-expressing SY5Y cells (TB8 cells) increases Akt activation and attenuates the cell death induced by chemotherapeutic reagents in the absence of BDNF. Furthermore, expression of a dominant-negative Akt (Akt-K179A) blocks the ability of BDNF to rescue TB8 cells from chemotherapy-induced cell death. Pharmacologic inhibition of Akt, with PIA6, a phosphatidylinositol ether lipid analogue (PIA), blocks BDNF-induced phosphorylation of Akt and the downstream target of Akt. PIA6 sensitizes neuroblastoma cells to chemotherapy and attenuates BDNF protection of neuroblastoma cells from chemotherapy-induced cell death. These results indicate that Akt is a key signaling component by which BDNF activation of the TrkB signal transduction pathway protects neuroblastoma cells from chemotherapy-induced cell death. This study raises the possibility that novel pharmacologic inhibitors of Akt may enhance the effectiveness of chemotherapeutic agents in the treatment of neuroblastoma tumors.

Key Words: neuroblastoma • BDNF • TrkB • Akt • chemotherapy

This article has been cited by other articles:

				C. J. Thiele, Z. Li, and A. E. McKee On Trk--The TrkB Signal Transduction Pathway Is an Increasingly Important Target in Cancer Biology Clin. Cancer Res., October 1, 2009; 15(19): 5962 - 5967. [Abstract] [Full Text] [PDF]

				P. Obexer, J. Hagenbuchner, T. Unterkircher, N. Sachsenmaier, C. Seifarth, G. Bock, V. Porto, K. Geiger, and M. Ausserlechner Repression of BIRC5/Survivin by FOXO3/FKHRL1 Sensitizes Human Neuroblastoma Cells to DNA Damage-induced Apoptosis Mol. Biol. Cell, April 1, 2009; 20(7): 2041 - 2048. [Abstract] [Full Text] [PDF]

				Z. Li, F. Tan, and C. J. Thiele Inactivation of glycogen synthase kinase-3 contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells Mol. Cancer Ther., December 1, 2007; 6(12): 3113 - 3121. [Abstract] [Full Text] [PDF]

				L.-Z. Liu, X.-D. Zhou, G. Qian, X. Shi, J. Fang, and B.-H. Jiang AKT1 Amplification Regulates Cisplatin Resistance in Human Lung Cancer Cells through the Mammalian Target of Rapamycin/p70S6K1 Pathway Cancer Res., July 1, 2007; 67(13): 6325 - 6332. [Abstract] [Full Text] [PDF]

				L. K. Martens, K. M. Kirschner, C. Warnecke, and H. Scholz Hypoxia-inducible Factor-1 (HIF-1) Is a Transcriptional Activator of the TrkB Neurotrophin Receptor Gene J. Biol. Chem., May 11, 2007; 282(19): 14379 - 14388. [Abstract] [Full Text] [PDF]

				D. Opel, C. Poremba, T. Simon, K.-M. Debatin, and S. Fulda Activation of Akt Predicts Poor Outcome in Neuroblastoma Cancer Res., January 15, 2007; 67(2): 735 - 745. [Abstract] [Full Text] [PDF]

				K. Nakamura, K. C. Martin, J. K. Jackson, K. Beppu, C.-W. Woo, and C. J. Thiele Brain-Derived Neurotrophic Factor Activation of TrkB Induces Vascular Endothelial Growth Factor Expression via Hypoxia-Inducible Factor-1{alpha} in Neuroblastoma Cells. Cancer Res., April 15, 2006; 66(8): 4249 - 4255. [Abstract] [Full Text] [PDF]