| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Medicine Branch, Division of Cancer Treatment [S. S., K. W., P. G., S. E. B.], and Cell and Molecular Biology Section, Pediatric Branch [P. V., E. L., C. J. T.], National Cancer Institute, Bethesda, Maryland 20892, and Laboratory of Cell and Biochemical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10021 [J. L. B., B. A. S.]
Brain-derived neurotrophic factor (BDNF) and its receptors are necessary for the survival and development of many neuronal cells. Because BDNF and TrkB are expressed in many poor-prognosis neuroblastoma (NB) tumors, we evaluated the role of BDNF in affecting sensitivity to chemotherapeutic agents. We investigated the effects of activation of the BDNF-TrkB signal transduction pathway in two NB cell lines, 15N and SY5Y. 15N cells lack the high-affinity receptor p145TrkB and express BDNF; 15N cells were used along with 15N-TrkB cells, a subline trans-fected with a TrkB expression vector. In cytotoxicity assays, 15N-TrkB cells were consistently 1.4–2-fold more resistant to vinblastine than 15N cells. Drug accumulation assays showed a 50% reduction in [3H]vinblastine accumulation in 15N-TrkB cells compared with control 15N cells. Addition of 30 ng/ml BDNF resulted in a reduction to 46% of control in 15N cells and a reduction to 28% of control in 15N-TrkB cells. SY5Y cells were chosen as a second model because they lack both endogenous BDNF and TrkB expression. p145TrkB expression is induced by 1 nM retinoic acid. Vinblastine accumulation was not significantly affected by 1 nM retinoic acid in SY5Y cells. Addition of 30 ng/ml BDNF decreased [3H]vinblastine accumulation to 58% of control in SY5Y cells and decreased [3H]vinblastine accumulation to 62% of control in TrkB-expressing SY5Y cells. Although an increase in BDNF expression is seen in multidrug-resistant sublines of SY5Y and BE(2)-C NB cells, the protective effect of BDNF in vinblastine toxicity may be unrelated to mdr-1, because the activity of other agents transported by P-glycoprotein was not affected. There was no increase in mdr-1 expression in 1 nM RA SY5Y cells and 15N-TrkB cells, as assessed by Northern blot analysis. In addition to the effects of BDNF on vinblastine cytotoxicity and accumulation, there was an inhibition in the ability of vinblastine to depolymerize tubulin in BDNF-treated cells. Thus, BDNF and TrkB may partially rescue NB cells from vinblastine toxicity and thereby may contribute to a more chemoresistant phenotype.
1 To whom requests for reprints should be addressed, at Cell and Molecular Biology Section, Pediatric Branch, National Cancer Institute, Bethesda, MD 20892. Phone: (301) 496–1543; Fax: (301) 402–0575; E-mail: thielec@pbmac.nci.nih.gov.
Received 11/27/95. Accepted 6/ 7/96.
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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 A. M. Monjazeb, K. P. High, A. Connoy, L. S. Hart, C. Koumenis, and F. H. Chilton Arachidonic acid-induced gene expression in colon cancer cells Carcinogenesis, October 1, 2006; 27(10): 1950 - 1960. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
Z. Li, J. Jaboin, P. A. Dennis, and C. J. Thiele Genetic and Pharmacologic Identification of Akt as a Mediator of Brain-Derived Neurotrophic Factor/TrkB Rescue of Neuroblastoma Cells from Chemotherapy-Induced Cell Death Cancer Res., March 15, 2005; 65(6): 2070 - 2075. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Jaboin, C. J. Kim, D. R. Kaplan, and C. J. Thiele Brain-derived Neurotrophic Factor Activation of TrkB Protects Neuroblastoma Cells from Chemotherapy-induced Apoptosis via Phosphatidylinositol 3'-Kinase Pathway Cancer Res., November 15, 2002; 62(22): 6756 - 6763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Eggert, M. A. Grotzer, N. Ikegaki, H. Zhao, A. Cnaan, G. M. Brodeur, and A. E. Evans Expression of the Neurotrophin Receptor TrkB Is Associated With Unfavorable Outcome in Wilms' Tumor J. Clin. Oncol., February 1, 2001; 19(3): 689 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Kim, T. Matsuo, K.-H. Lee, and C. J. Thiele Up-Regulation of Insulin-Like Growth Factor-II Expression Is a Feature of TrkA but Not TrkB Activation in SH-SY5Y Neuroblastoma Cells Am. J. Pathol., November 1, 1999; 155(5): 1661 - 1670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Middlemas, B. K. Kihl, J. Zhou, and X. Zhu Brain-derived Neurotrophic Factor Promotes Survival and Chemoprotection of Human Neuroblastoma Cells J. Biol. Chem., June 4, 1999; 274(23): 16451 - 16460. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Simizu, M. Takada, K. Umezawa, and M. Imoto Requirement of Caspase-3(-like) Protease-mediated Hydrogen Peroxide Production for Apoptosis Induced by Various Anticancer Drugs J. Biol. Chem., October 9, 1998; 273(41): 26900 - 26907. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
