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 Ho, R. Articles by Brodeur, G. M. Search for Related Content PubMed PubMed Citation Articles by Ho, R. Articles by Brodeur, G. M.

Resistance to Chemotherapy Mediated by TrkB in Neuroblastomas¹

Division of Oncology, the Children’s Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania 19104 [R. H., A. E., T. H., J.E.M, N. I., P. F., A. E. E., G. M. B.], and Cephalon, Inc, West Chester, Pennsylvania 19380 [A. M. C.]

Neuroblastoma is a common childhood tumor derived from the peripheral nervous system. Favorable neuroblastomas usually express TrkA, the receptor for nerve growth factor (NGF), whereas unfavorable, MYCN-amplified neuroblastomas usually express TrkB and its ligand, brain-derived neurotrophic factor (BDNF). Here, we provide evidence that the TrkB-BDNF pathway is associated with enhanced survival and resistance to chemotherapy in neuroblastoma. We transfected the neuroblastoma line SH-SY5Y, which has endogenous expression of BDNF, with a full-length TrkB expression vector, and obtained clones with moderate or high levels of expression. Cells were exposed in vitro to chemotherapy agents used to treat neuroblastomas: doxorubicin, etoposide (VP16), and cisplatin. Chemoresistance was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cell survival and by ELISA for cell death. In all cases, the TrkB-expressing subclones were more resistant to treatment than the parent line. Furthermore, when the TrkB tyrosine kinase was blocked with the Trk-specific inhibitor CEP-2563, or by neutralizing antibody to BDNF, sensitivity to chemotherapy was significantly increased. We also found constitutive phosphorylation of AKT at the Ser-473 site in TrkB transfectants, whereas there was only a minimal level of constitutive phosphorylation of AKT in SY5Y cells. These results show that the TrkB-BDNF pathway provides a survival advantage when exposed to DNA-damaging reagents, and, therefore, this autocrine pathway may play an important role in mediating the drug-resistant phenotype associated with TrkB-expressing neuroblastomas. Activation of PI3K/AKT survival pathway may contribute to the increased drug resistance in TrkB-expressing neuroblastomas.

This article has been cited by other articles:

				T. Van Maerken, L. Ferdinande, J. Taildeman, I. Lambertz, N. Yigit, L. Vercruysse, A. Rihani, M. Michaelis, J. Cinatl Jr, C. A. Cuvelier, et al. Antitumor Activity of the Selective MDM2 Antagonist Nutlin-3 Against Chemoresistant Neuroblastoma With Wild-Type p53 J Natl Cancer Inst, November 10, 2009; (2009) djp355v1. [Abstract] [Full Text] [PDF]

				K. Thress, T. MacIntyre, H. Wang, D. Whitston, Z.-Y. Liu, E. Hoffmann, T. Wang, J. L. Brown, K. Webster, C. Omer, et al. Identification and preclinical characterization of AZ-23, a novel, selective, and orally bioavailable inhibitor of the Trk kinase pathway Mol. Cancer Ther., July 1, 2009; 8(7): 1818 - 1827. [Abstract] [Full Text] [PDF]

				G. M. Brodeur, J. E. Minturn, R. Ho, A. M. Simpson, R. Iyer, C. R. Varela, J. E. Light, V. Kolla, and A. E. Evans Trk Receptor Expression and Inhibition in Neuroblastomas Clin. Cancer Res., May 15, 2009; 15(10): 3244 - 3250. [Abstract] [Full Text] [PDF]

				Z. Li, G. Beutel, M. Rhein, J. Meyer, C. Koenecke, T. Neumann, M. Yang, J. Krauter, N. von Neuhoff, M. Heuser, et al. High-affinity neurotrophin receptors and ligands promote leukemogenesis Blood, February 26, 2009; 113(9): 2028 - 2037. [Abstract] [Full Text] [PDF]

				B. Gabriele and T. Enrico BDNF splice variants from the second promoter cluster support cell survival of differentiated neuroblastoma upon cytotoxic stress J. Cell Sci., January 1, 2009; 122(1): 36 - 43. [Abstract] [Full Text] [PDF]

				D. Boller, A. Schramm, K. T. Doepfner, T. Shalaby, A. O. von Bueren, A. Eggert, M. A. Grotzer, and A. Arcaro Targeting the Phosphoinositide 3-Kinase Isoform p110{delta} Impairs Growth and Survival in Neuroblastoma Cells Clin. Cancer Res., February 15, 2008; 14(4): 1172 - 1181. [Abstract] [Full Text] [PDF]

				Y. Xie, H. Chan, J. Fan, Y. Chen, J. Young, W. Li, X. Miao, Z. Yuan, H. Wang, P. K.H. Tam, et al. Involvement of visinin-like protein-1 (VSNL-1) in regulating proliferative and invasive properties of neuroblastoma Carcinogenesis, October 1, 2007; 28(10): 2122 - 2130. [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]

				T. Khan, J. A. Hixon, J. K. Stauffer, E. Lincoln, T. C. Back, J. Brenner, S. Lockett, K. Nagashima, D. Powell, and J. M. Wigginton Therapeutic Modulation of Akt Activity and Antitumor Efficacy of Interleukin-12 Against Orthotopic Murine Neuroblastoma J Natl Cancer Inst, February 1, 2006; 98(3): 190 - 202. [Abstract] [Full Text] [PDF]

				M. Hecht, J. H. Schulte, A. Eggert, J. Wilting, and L. Schweigerer The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness Carcinogenesis, December 1, 2005; 26(12): 2105 - 2115. [Abstract] [Full Text] [PDF]

				R. Ho, J. E. Minturn, T. Hishiki, H. Zhao, Q. Wang, A. Cnaan, J. Maris, A. E. Evans, and G. M. Brodeur Proliferation of Human Neuroblastomas Mediated by the Epidermal Growth Factor Receptor Cancer Res., November 1, 2005; 65(21): 9868 - 9875. [Abstract] [Full Text] [PDF]

				T. R. Geiger and D. S. Peeper The Neurotrophic Receptor TrkB in Anoikis Resistance and Metastasis: A Perspective Cancer Res., August 15, 2005; 65(16): 7033 - 7036. [Abstract] [Full Text] [PDF]

				J.-F. Lavoie, L. LeSauteur, J. Kohn, J. Wong, O. Furtoss, C. J. Thiele, F. D. Miller, and D. R. Kaplan TrkA Induces Apoptosis of Neuroblastoma Cells and Does So via a p53-dependent Mechanism J. Biol. Chem., August 12, 2005; 280(32): 29199 - 29207. [Abstract] [Full Text] [PDF]

				E. Terui, T. Matsunaga, H. Yoshida, K. Kouchi, H. Kuroda, T. Hishiki, T. Saito, S.-i. Yamada, H. Shirasawa, and N. Ohnuma Shc Family Expression in Neuroblastoma: High Expression of shcC Is Associated with a Poor Prognosis in Advanced Neuroblastoma Clin. Cancer Res., May 1, 2005; 11(9): 3280 - 3287. [Abstract] [Full Text] [PDF]

				B. Sitek, O. Apostolov, K. Stuhler, K. Pfeiffer, H. E. Meyer, A. Eggert, and A. Schramm Identification of Dynamic Proteome Changes Upon Ligand Activation of Trk-Receptors Using Two-dimensional Fluorescence Difference Gel Electrophoresis and Mass Spectrometry Mol. Cell. Proteomics, March 1, 2005; 4(3): 291 - 299. [Abstract] [Full Text] [PDF]

				Z. F. Yang, D. W. Ho, C. T. Lam, J. M. Luk, C. T. Lum, W. C. Yu, R. T. Poon, and S. T. Fan Identification of Brain-Derived Neurotrophic Factor as a Novel Functional Protein in Hepatocellular Carcinoma Cancer Res., January 1, 2005; 65(1): 219 - 225. [Abstract] [Full Text] [PDF]