Skip to main content
SpringerLink
Log in

Brain Derived Neurotrophic Factor Protects Human Neuroblastoma Cells from DNA Damaging Agents

  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Neurotrophins are required for survival of neurons during development and may act as survival factors to cells undergoing stress. We tested whether brain derived neurotrophic factor (BDNF) protects neuroblastoma (NB) cells from cytotoxic agents using a model NB cell line, NB 1643, which expresses functional tropomyosin related kinase B (TRKB) following treatment with all-trans-retinoic acid. TRKB is the receptor for BDNF. BDNF increases the EC50 values in survival assays for cisplatin, doxorubicin, and topotecan by two to three fold. Thus, BDNF does indeed protect cells drugs that damage DNA. Cisplatin and doxorubicin are used to treat NB. Topotecan is in clinical studies for the treatment of NB. Since these drugs induce DNA damage, we also investigated whether BDNF might afford protection from γ irradiation. BDNF also induces more than a two fold resistance to γ irradiation. Since BDNF protects cells from agents with different mechanisms of damaging DNA and resistance, it seems likely that BDNF may alter a common signaling pathway required for cell death initiation by DNA damaging agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Matthay KK: Neuroblastoma: a clinical challenge and biologic puzzle. CA Cancer J Clin 45: 179–192, 1995

    Google Scholar 

  2. Israel MA: Tumor cell lines of the peripheral nervous system, Atlas of Human Tumor Cell Lines. 1994, pp 42–78

  3. Levi-Montalcini R: Effects of mouse tumor transplantation on the nervous system. AnnNYAcad Sci 55: 330–343, 1952

    Google Scholar 

  4. Levi-Montalcini R: Developmental neurobiology and the natural history of nerve growth factor. Annu Rev Neurosci 5: 341–362, 1982

    Google Scholar 

  5. Cohen S, Levi-Montalcini R, Hamburger V: A nerve growth stimulating factor isolated from sarcoma 37 and 180. Proc Natl Acad Sci USA 40: 1014–1018, 1954

    Google Scholar 

  6. Barde YA, Edgar D, Thoenen H: Purification of a new neurotrophic factor from mammalian brain. Embo J 1: 549–553, 1982

    Google Scholar 

  7. Leibrock J, Lottspeich F, Hohn A, Hofter M, Hengerer B, Masiakowski P et al.: Molecular cloning and expression of brain-derived neurotrophic factor. Nature 341: 149–152, 1989

    Google Scholar 

  8. Kaplan DR, Martin-Zanca D, Parada LF: Tyrosine phosphorylation and tyrosine kinase activity of the trk protooncogene product induced by NGF. Nature 350: 158–160, 1991

    Google Scholar 

  9. Kaplan DR, Hempstead BL, Martin-Zanca D, Chao MV, Parada LF: The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 252: 554–558, 1991

    Google Scholar 

  10. Klein R, Jing SQ, Nanduri V, O'Rourke E, Barbacid M: The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 65: 189–197, 1991

    Google Scholar 

  11. Soppet D, Escandon E, Maragos J, Middlemas DS, Reid SW, Blair J et al.: The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Cell 65: 895–903, 1991

    Google Scholar 

  12. Squinto SP, Stitt TN, Aldrich TH, Davis S, Bianco SM, Radziejewski C et al.: trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor. Cell 65: 885–893, 1991

    Google Scholar 

  13. Klein R, Nanduri V, Jing SA, Lamballe F, Tapely P, Bryant S et al.: The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell 66: 395–403, 1991

    Google Scholar 

  14. Middlemas DS: Receptor protein-tryosine kinases in the nervous system, cloning and expression of trkB. Meth Neurosci 12: 139–155, 1993

    Google Scholar 

  15. Middlemas DS, Meisenhelder J, Hunter T: Identification of TrkB autophosphorylation sites and evidence that phospholipase C-1 is a substrate of the TrkB receptor. J Biol Chem 269: 5458–5466, 1994

    Google Scholar 

  16. Smeyne RJ, Klein R, Schnapp A, Long LK, Bryant S, Lewin A et al.: Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene. Nature 368: 246–249, 1994

    Google Scholar 

  17. Klein R, Martin-Zanca D, Barbacid M, Parada LF: Expression of the tyrosine kinase receptor gene trkB is confined to the murine embryonic and adult nervous system. Development 109: 845–850, 1990

    Google Scholar 

  18. Klein R: Role of neurotrophins in mouse neuronal development. Faseb J 8: 738–744, 1994

    Google Scholar 

  19. Klein R, Smeyne RJ, Wurst W, Long LK, Auerbach BA, Joyner AL, et al.: Targeted disruption of the trkB neurotrophin receptor gene results in nervous system lesions and neonatal death. Cell 75: 113–122, 1993

    Google Scholar 

  20. Pinon LG, Minichiello L, Klein R, Davies AM: Timing of neuronal death in trkA, trkB and trkC mutant embryos reveals developmental changes in sensory neuron dependence on TrK signalling, Development 122: 3255–3261, 1996

    Google Scholar 

  21. Acheson A, Conover JC, Fandl JP, DeChiara TM, Russell M, Thadani A et al.: A BDNF autocrine loop in adult sensory neurons prevents cell death (see comments). Nature 374: 450–453, 1995

    Google Scholar 

  22. Nakagawara A, Arima-Nakagawara M, Scavarda NJ, Azar CG, Cantor AB, Brodeur GM: Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 328: 847–854, 1993

    Google Scholar 

  23. Kogner P, Barbany G, Dominici C, Castello MA, Raschella G, Persson H: Coexpression of messenger RNA for TRK protooncogene and lowaffinity nerve growth factor receptor in neuroblastoma with favorable prognosis. Cancer Res 53: 2044–2050, 1993

    Google Scholar 

  24. Suzuki T, Bogenmann E, Shimada H, Stram D, Seeger RC: Lack of high-affinity nerve growth factor receptors in aggressive neuroblastomas. J Natl Cancer Inst 85: 377–384, 1993

    Google Scholar 

  25. Nakagawara A, Arima M, Azar CG, Scavarda NJ, Brodeur GM: Inverse relationship between trk expression and N-myc amplification in human neuroblastomas. Cancer Res 52: 1364–1368, 1992

    Google Scholar 

  26. Borrello MG, Bongarzone I, Pierotti MA, Luksch R, Gasparini M, Collini P et al.: trk and ret proto-oncogene expression in human neuroblastoma specimens: high frequency of trk expression in non-advanced stages. Int J Cancer 54: 540–545, 1993

    Google Scholar 

  27. Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM: Amplication of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224: 1121–1124, 1984

    Google Scholar 

  28. Nakagawara A, Azar CG, Scavarda NJ, Brodeur GM: Expression and function of TRK-B and BDNF in human neuroblastomas. Mol Cell Biol 14: 759–767, 1994

    Google Scholar 

  29. Frisen J, Verge VM, Cullheim S, Persson H, Fried K, Middlemas DS et al.: Increased levels of trkB mRNA and trkB protein-like immunoreactivity in the injured rat and cat spinal cord. Proc Natl Acad Sci USA 89: 11282–11286, 1992

    Google Scholar 

  30. Merlio JP, Ernfors P, Kokaia Z, Middlemas DS, Bengzon J, Kokaia M et al.: Increased production of the TrkB protein tyrosine kinase receptor after brain insults. Neuron 10: 151–164, 1993.

    Google Scholar 

  31. Frisen J, Verge VM, Fried K, Risling M, Persson H, Trotter J et al.: Characterization of glial trkB receptors: differential response to injury in the central and peripheral nervous systems. Proc Natl Acad Sci USA 90: 4971–4975, 1993

    Google Scholar 

  32. Dugich-Djordjevic MM, Ohsawa F, Okazaki T, Mori N, Day JR, Beck KD et al.: Differential regulation of catalytic and non-catalytic trkB messengerRNAs in the rat hippocampus following seizures induced by systemic administration of kainate. Neuroscience 66: 861–877, 1995

    Google Scholar 

  33. Cheng B, Mattson MP: NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Res 640: 56–67, 1994

    Google Scholar 

  34. Ghosh A, Carnahan J, Greenberg ME: Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263: 1618–1623, 1994

    Google Scholar 

  35. Alcantara S, Frisen J, del Rio JA, Soriano E, Barbacid M, Silos-Santiago I: TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death. J Neurosci 17: 3623–3633, 1997

    Google Scholar 

  36. Thompson J, Zamboni W, Cheshire P, Lutz L, Luo X, Li Y et al.: Efficacy of systemic administration of irinotecan against neuroblastoma xenografts. Clin Cancer Res 3: 423–431, 1997

    Google Scholar 

  37. Middlemas DS, Kihl BK, Zhou J, Zhu X: Brain derived neurotrophic factor promotes survival and chemoprotection of human neuroblastoma cells. J Biol Chem 274: 16451–16460, 1999

    Google Scholar 

  38. Butler WB: Preparing nuclei from cells in monolayer suitable for counting and following synchronized cells through cell cycle. Anal Biochem 141: 70–73, 1984

    Google Scholar 

  39. Thimmaiah KN, Horton JK, Qian XD, Beck WT, Houghton JA, Houghton PJ: Structural determinants of phenoxazine type compounds required to modulate the accumulation of vinblastine and vincristine in multidrug-resistant cell lines. Cancer Commun 2: 249–259, 1990

    Google Scholar 

  40. Zar JH (ed): Comparing simple linear regression equations. In: Biostatistical Analysis. Chapter 18. Prentice-Hall, Englewood Cliffs, NJ, 1984, pp 292–305

  41. Reed E, Dabholkar M, Chabner B: Platinum analogues. In: Chabner B, Longo DL (eds) Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott-Raven, Philapdelphia, 1996, pp 357–378

    Google Scholar 

  42. Doroshow JH: Anthracyclines and anthracenediones. In Chabner B, Longo DL (eds) Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott-Raven, Philadelphia, 1996, pp 409–434

    Google Scholar 

  43. Takimoto CH, Arbuck SG: The camptothecins. In Chabner B, Longo DL (eds) Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott-Raven, Philapdelphia, 1996, pp 463–484

    Google Scholar 

  44. Brenner DJ, Ward JF: Constraints on energy deposition and target size of multiply damaged sites associated with DNA double-strand breaks. Int J Radiat Biol 61: 737–748, 1992

    Google Scholar 

  45. Radford IR: The level of inducedDNAdouble-strand breakage correlates with cell killing after X-irradiation. Int J Radiat Biol Relat Stud Phys Chem Med 48: 45–54, 1985

    Google Scholar 

  46. Beck W: Drug accumulation and binding in P-glycoproteinassociated multidrug resistance. In: Roninson IB (ed) Molecular and Cellular Biology of Multidrug Resistance in Tumor Cells. Plenum Press, New York, 1991, pp 215–227

    Google Scholar 

  47. Obermeier A, Halfter H, Wiesmuller KH, Jung G, Schlessinger J, Ullrich A: Tyrosine 785 is a major determinant of Trk-substrate interaction. Embo J 12: 933–941, 1993

    Google Scholar 

  48. Vetter ML, Martin-Zanca D, Parada LF, Bishop JM, Kalpan DR: Nerve growth factor rapidly stimulates tyrosine phosphorylation of phospholipase C-1 by a kinase activity associated with the product of the trk protooncogene. Proc Natl Acad Sci USA 88: 5650–5654, 1991

    Google Scholar 

  49. Basu T, Warne PH, Downward J: Role of Shc in the activation of Ras in response to epidermal growth factor and nerve growth factor. Oncogene 9: 3483–3491, 1994

    Google Scholar 

  50. Obermeier A, Lammers R, Wiesmuller KH, Jung G, Schlessinger J, Ullrich A: Identification of Trk binding sites of SHC and phosphatidylinositol 30-kinase and formation of a multimeric signaling complex. J Biol Chem 268: 22963–22966, 1993

    Google Scholar 

  51. Ohmichi M, Decker SJ, Saltiel AR: Activitation of phosphatidylinositol-3-kinase by nerve growth factor involves indirect coupling of the trk proto-oncogene with src homology 2 domains. Neuron 9: 769–777, 1992

    Google Scholar 

  52. Holgado-Madruga M, Moscatello DK, Emlet DR, Dieterich R, Wong AJ: Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor. Proc Natl Acad Sci USA 94: 12419–12424, 1997

    Google Scholar 

  53. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ et al.: Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370: 527–532, 1994

    Google Scholar 

  54. Easton JE, Moody NE, Zhu X, Middlemas DS: Brain derived neurotrophic factor induces phosphorylation of fibroblast growth factor receptor substrate 2. J Biol Chem 274: 11321–11327, 1999

    Google Scholar 

  55. Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I et al.: A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89: 693–702, 1997

    Google Scholar 

  56. Hadari YR, Kouhara H, Lax I, Schlessinger J: Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. Mol Cell Biol 18: 3966–3973, 1998

    Google Scholar 

  57. Rabin SJ, Cleghon V, Kaplan DR: SNT, a differentiationspecific target of neurotrophic factor-induced tyrosine kinase activity in neurons and PC12 cells. Mol Cell Biol 13: 2203–2213, 1993

    Google Scholar 

  58. Peng X, Greene LA, Kaplan DR, Stephens RM: Deletion of a conserved juxtamembrane sequence in Trk abolishes NGF-promoted neuritogenesis. Neuron 15: 395–406, 1995

    Google Scholar 

  59. Qian X, Riccoio A, Zhang Y, Ginty DD: Identification and characterization of novel substrates of Trk receptors in devoloping neurons. Neuron 21: 1017–1029, 1998

    Google Scholar 

  60. Matsumoto K, Wada RK, Yamashiro JM, Kalpan DR, Thiele CJ: Expression of brain-derived neurotrophic factor and p145TrkB affects survival, differentiation, and invasiveness of human neuroblastoma cells. Cancer Res 55: 1798–1806, 1995

    Google Scholar 

  61. Scala S, Wosikowski K, Giannakakou P, Valle P, Biedler JL, Spengler BA et al.: Brain-derived neurotrophic factor protects neuroblastoma cells from vinblastine toxicity. Cancer Res 56: 3737–3742, 1996

    Google Scholar 

  62. Lasorella A, Iavarone A, Israel MA: Differentiation of neuroblastoma enhances Bcl-2 expression and induces alterations of apoptosis and drug resistance. Cancer Res 55: 4711–4716, 1995

    Google Scholar 

  63. Kaplan DR, Matsumoto K, Lucarelli E, Thiele CJ: Induction of TrkB by retinoic acid mediates biologic responsiveness to BDNF and differentiation of human neuroblastoma cells. Neuron 11: 321–331, 1993

    Google Scholar 

  64. Torres-Aleman I, Pons S, Arevalo MA: The insulin-like growth factor I system in the rat cerebellum: developmental regulation and role in neuronal survival and differentiation. J Neurosci Res 39: 117–126, 1994

    Google Scholar 

  65. Nakao N, Odin P, Lindvall O, Brundin P: Differential trophic effects of basic fibroblast growth factor, insulin-like growth factor-1, and neurotrophin-3 on striatal neurons in culture. Exp Neurol 138: 144–157, 1996

    Google Scholar 

  66. Zawada WM, Kirschman DL, Cohen JJ, Heidenreich KA, Freed CR: Growth factors rescue embryonic dopamine neurons from programmed cell death. Exp Neurol 140: 60–67, 1996

    Google Scholar 

  67. Frodin M, Gammeltoft S: Insulin-like growth factors act synergistically with basic fibroblast growth factor and nerve growth factor to promote chromaffin cell proliferation. Proc Natl Acad Sci USA 91: 1771–1775, 1994

    Google Scholar 

  68. Sell C, Baserga R, Rubin R: Insulin-like growth factor I (IGF-I) and the IGF-I receptor prevent etoposide-induced apoptosis. Cancer Res 55: 303–306, 1995

    Google Scholar 

  69. Geier A, Beery R, Haimsohn M, Karasik A; Insulin-like growth factor-1 inhibits cell death induced by anticancer drugs in the MCF-7 cells: involvement of growth factors in drug resistance. Cancer Invest 13: 480–486, 1995

    Google Scholar 

  70. Minshall C, Arkins S, Freund GG, Kelley KW: Requirement for phosphatidylinositol 3?-kinase to protect hemopoietic progenitors against apoptosis depends upon the extracellular survival factor. J Immunol 156: 939–947, 1996

    Google Scholar 

  71. Vermuri GS, McMorris FA: Oligodendrocytes and their precursors require phosphatidylinositol 3-kinase signaling for survival. Development 122: 2529–2537, 1996

    Google Scholar 

  72. Yao R, Cooper GM: Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 267: 2003–2006, 1995

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Pharmacology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN, USA

    David S. Middlemas, Brenda K. Kihl & Norma M. Moody

Authors
  1. David S. Middlemas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brenda K. Kihl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Norma M. Moody
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Middlemas, D.S., Kihl, B.K. & Moody, N.M. Brain Derived Neurotrophic Factor Protects Human Neuroblastoma Cells from DNA Damaging Agents. J Neurooncol 45, 27–36 (1999). https://doi.org/10.1023/A:1006342423175

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006342423175

Search

Navigation