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NF-κB controls growth of glioblastomas/astrocytomas

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Abstract

NF-κB is a family of transcription factors that have been shown to be elevated in a variety of tumor types and in some cases central to their survival and growth. Here we present evidence that U-87 MG and U-118 MG growth is regulated by NF-κB and controlled by PDGF. NF-κB activity was suppressed by a dominant negative mutant of the human PDGF type β receptor and PDGF-B chain neutralizing antibodies. Creation of cell lines that had inducible expression of shRNAs directed against either c-Rel or RelA inhibited growth almost 90% indicating that NF-κB plays a central role in glioblastoma growth.

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References

  1. Bywater M, Rorsman F, Bongcam-Rudloff E et al (1988) Expression of recombinant platelet-derived growth factor A- and B-chain homodimers in rat-1 cells and human fibroblasts reveals differences in protein processing and autocrine effects. Mol Cell Biol 8:2753–2762

    PubMed  CAS  Google Scholar 

  2. Heldin C-H, Backstrom G, Ostman A et al (1989) Binding of different dimeric forms of PDGF to human fibroblasts: evidence for two separate receptor types. EMBO J 7:1387–1393

    Google Scholar 

  3. LaRochelle WJ, Jeffers M, McDonald WF et al (2001) PDGF-D, a new protease-activated growth factor. Nat Cell Biol 3:517–521

    Article  PubMed  CAS  Google Scholar 

  4. Bergsten E, Uutela M, Li X et al (2001) PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. Nat Cell Biol 3:512–516

    Article  PubMed  CAS  Google Scholar 

  5. Deuel TF (1988) Polypeptide growth factors: roles in normal and abnormal cell growth. Ann Rev Cell Biol 3:443–492

    Google Scholar 

  6. Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor Physiol Rev 79:1283–316

    PubMed  CAS  Google Scholar 

  7. Li X, Ponten A, Aase K et al (2000) PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor Nat Cell Biol 2:302–9

    Article  PubMed  CAS  Google Scholar 

  8. Arvidsson A-K, Rupp E, Nanberg E et al (1994) Tyr-716 in the platelet-derived growth factor b-receptor kinase insert is involved in GRB2 binding and ras activation. Mol Cell Biol 14:6715–6726

    PubMed  CAS  Google Scholar 

  9. Yokote K, Mori S, Hansen K et al (1994) Direct interaction between Shc and the platelet-derived growth factor b receptor. J Biol Chem 269:15337–15343

    PubMed  CAS  Google Scholar 

  10. Yokote K, Margolis B, Heldin C-H et al (1996) Grb7 is a downstream signaling component of platelet-derived growth factor a and b receptors. J Biol Chem 271:30942–30949

    Article  PubMed  CAS  Google Scholar 

  11. Yokote K, Hellman U, Ekman S et al (1998) Identification of Tyr-762 in the platelet-derived factor a-receptor as the binding site for Crk proteins. Oncogene 16:1229–1239

    Article  PubMed  CAS  Google Scholar 

  12. Li W, Nishimura R, Kashishian A et al (1994) A new function for a phosphotyrosine phosphatase: linking GRB2-SOS to a receptor tyrosine kinase. Mol Cell Biol 14:509–517

    PubMed  CAS  Google Scholar 

  13. Kashishian A, Cooper JA (1993) Phosphorylation sites at the C-terminus of the platelet-derived growth factor receptor bind phospholipase Cg1. Mol Cell Biol 4:49–57

    CAS  Google Scholar 

  14. Escobedo JA, Kaplan DR, Kavanaugh WM et al (1991) A phosphotidylinositol-3 kinase binds to platelet-derived growth factor receptors through a specific receptor sequence containing phosphotyrosine. Mol Cell Biol 11:1125–1132

    PubMed  CAS  Google Scholar 

  15. Escobedo JA, Navankasattusas S, Kavanaugh WM et al (1991) cDNA cloning of a novel 85 kd protein that has SH2 domains and regulates binding of PI3-kinase to the PDGF β-receptor. Cell 65:75–82

    Article  PubMed  CAS  Google Scholar 

  16. Kypta RM, Goldberg Y, Ulug ET et al (1990) Association between the PDGF receptor and members of the src family of tyrosine kinases. Cell 62:481–492

    Article  PubMed  CAS  Google Scholar 

  17. Mori S, Roonstrand L, Yokote K et al (1993) Identification of two juxtamembrane autophosphorylation sites in the PDGF b-receptor; involvement in the interaction with Src family tyrosine kinases. EMBO J 12:2257–2264

    PubMed  CAS  Google Scholar 

  18. Kazlauskas A, Feng G-S, Pawson T et al (1993) The 64-kDa protein that associates with the platelet-derived growth factor receptor b subunit via Tyr-1009 is the SH2-containing phosphotyrosine phosphatase Syp. Proc Nat Acad Sci 90:6939–6942

    Article  PubMed  CAS  Google Scholar 

  19. Ronnstrand L, Mori S, Arridsson AK et al (1992) Identification of two C-terminal autophosphorylation sites in the PDGF b-receptor:involvement in the interaction with phospholipase C-g. EMBO J 11:3911–3919

    PubMed  CAS  Google Scholar 

  20. Rozengurt E, Sinnett-Smith J, Taylor-Papadimitriou J (1985) Production of PDGF-like growth factor by breast cancer cell lines. Int J Cancer 36:247–252

    Article  PubMed  CAS  Google Scholar 

  21. Bronzert DA, Pantazis P, Antoniades HN et al (1987) Synthesis and secretion of platelet-derived growth factor by human breast cancer cell lines. Proc Nat Acad Sci USA 84:5763–5767

    Article  PubMed  CAS  Google Scholar 

  22. Nister M, Claesson-Welch L, Eriksson A et al (1991) Differential expression of platelet-derived growth factor receptors in human malignant glioma cell lines. J Biol Chem 266:16755–16763

    PubMed  CAS  Google Scholar 

  23. Hsu S, Huang F, Friedman E (1995) Platelet-derived growth factor-B increases colon cancer cell growth in vivo by a paracrine effect. J Cell Phys 165:239–245

    Article  CAS  Google Scholar 

  24. De Jong JS, Van Diest PJ, Van Der Valk P et al (1998) Expression of growth factors, growth inhibiting factors, and their receptors in invasive breast cancer. I: an inventory in search of autocrine and paracrine loops. J Path 184:44–52

    Article  PubMed  Google Scholar 

  25. Lokker NA, Sullivan CM, Hollenbach SJ et al (2002) Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res 62:3729–3735

    PubMed  CAS  Google Scholar 

  26. Strawn LM, Mann E, Elliger SS et al (1994) Inhibition of glioma cell growth by a truncated platelet-derived growth factor-b receptor. J Biol Chem 269:21215–21222

    PubMed  CAS  Google Scholar 

  27. Shamah SM, Stiles CD, Guha A (1993) Dominant negative mutant of the platelet derived growth factor reverts the transformed phenotype of human astrocytoma cells. Mol Cell Biol 13:7203–7212

    PubMed  CAS  Google Scholar 

  28. Li W, Michieli P, Maurizio A et al (1996) Expression of an ATP binding mutant of PKC-δ inhibits Sis-induced transformation of NIH3T3. Cells Oncogene 13:731–737

    CAS  Google Scholar 

  29. DeMali KA, Whiteford CC, Ulug ET et al (1997) Platelet-derived Growth Factor-dependent cellular transformation requires either Phospholipase cg or Phosphatidylinositol 3 kinase. J Biol Chem 272:9011–9018

    Article  PubMed  CAS  Google Scholar 

  30. Gelderloos JA, Rosenkranz S, Bazenet C et al (1998) A role for Src in signal relay by the platelet-derived growth factor alpha receptor. J Biol Chem 273:5908–15

    Article  PubMed  CAS  Google Scholar 

  31. Nagase T, Kawata S, Nakajima H et al (1999) Effect of farnesyltransferase overexpression on cell growth and transformation. Int J Cancer 80:126–33

    Article  PubMed  CAS  Google Scholar 

  32. Bazenet CH, Gelderloos JA, Kazlauskas A (1996) Phosphorylation of tyrosine 720 in the platelet-derived growth factor a receptor is required for binding of grb2 and shp-2 but not for activation of ras and cellular proliferation. Mol Cell Biol 16:6926–6936

    PubMed  CAS  Google Scholar 

  33. Shimamura T, Hsu TC, Colburn NH et al (2002) Activation of NF-κB is required for PDGF-B Chain to transform NIH3T3 cells. Exp Cell Res 274:157–67

    Article  PubMed  CAS  Google Scholar 

  34. Baeuerle PA, Baltimore D (1996) NF-κB: ten years after. Cell 87:13–20

    Article  PubMed  CAS  Google Scholar 

  35. Baeuerle PA (1991) The inducible transcription activator NF-κB: regulation by distinct protein subunits. Biochem Biophys Acta 1072:63–80

    PubMed  CAS  Google Scholar 

  36. Ganchi PA, Sun SC, Greene WC et al (1992) I κB/MAD-3 masks the nuclear localization signal of NF-κB p65 and requires the transactivation domain to inhibit NF-κB p65 DNA binding. Mol Biol Cell 3:1339–1352

    PubMed  CAS  Google Scholar 

  37. Finco TS, Baldwin AS (1995) Mechanistic aspects of NF-κB regulation: the emerging role of phosphorylation and proteolysis. Immunity 3:263–272

    Article  PubMed  CAS  Google Scholar 

  38. Rice N, Ernst MK (1993) In vivo control of NF-κB activation by IκBα. EMBO J 12:4685–4695

    PubMed  CAS  Google Scholar 

  39. Silverman N, Maniatis T (2001) NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev 15:2321–2342

    Article  PubMed  CAS  Google Scholar 

  40. Hinz M, Krappmann D, Eichten A et al (1999) NF-κB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol 19:2690–2698

    Google Scholar 

  41. Karin M, Cao Y, Gretzen FR et al (2002) NF-κB in cancer: from innocent bystander to major culprit. Nature Cancer Rev 2:301–310

    Article  CAS  Google Scholar 

  42. Bargou RC, Emmerich F, Krappmann D et al (1997) Constitutive nuclear factor-κB-RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells. J Clin Invest 100:2961–2969

    Article  PubMed  CAS  Google Scholar 

  43. Shattuck-Brandt RL, Richmond A (1997) Enhanced degradation of I-κB alpha contributes to endogenous activation of NF-κB in Hs294T melanoma cells. Cancer Res 57:3032–3039

    PubMed  CAS  Google Scholar 

  44. Sovak MA, Bellas RE, Kim DW et al (1997) Aberrant nuclear factor-κB/Rel expression and the pathogenesis of breast cancer. J Clin Invest 100:2952–2960

    PubMed  CAS  Google Scholar 

  45. Palayoor ST, Youmell MY, Calderwood SK et al (1999) Constitutive activation of IκB kinase alpha and NF-κB in prostate cancer cells is inhibited by ibuprofen. Oncogene 18:7389–7394

    Article  PubMed  CAS  Google Scholar 

  46. Huang S, DeGuzman A, Bucana CD et al (2000) Nuclear factor-kappaB activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice. Clin Cancer Res 6:2573–2581

    PubMed  CAS  Google Scholar 

  47. Kordes U, Krappmann D, Heissmeyer V et al (2000) Transcription factor NF-κB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 14:399–402

    Article  PubMed  CAS  Google Scholar 

  48. Nagai S, Washiyama K, Kurimoto M et al (2002) Aberrant nuclear factor-kappaB activity and its participation in the growth of human malignant astrocytoma. J Neurosurg 96:909–917

    Article  PubMed  CAS  Google Scholar 

  49. Lu T, Stark GR (2004) Cytokine overexpressioin and consitiutive NF-κB in cancer Cell. Cycle 3:1114–1119

    PubMed  CAS  Google Scholar 

  50. Zhou Y, Yau C, Gray JW et al (2007) Enhanced NF-κB and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer 7:59

    Article  PubMed  CAS  Google Scholar 

  51. Duffey DC, Chen Z, Dong G et al (2000) Expression of a dominant-negative mutant inhibitor-kappaBalpha of nuclear factor-kappaB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo. Cancer Res 59:3468–3474

    Google Scholar 

  52. Gill JS, Zhu X, Moore MJ et al (2002) Effects of NF-κB decoy oligonucleotides released from biodegradable polymer microparticles on a glioblastoma cell line. Biomaterials 23:2773–2781

    Article  PubMed  CAS  Google Scholar 

  53. Murphy K, Shimamura T, Bejcek BE (2001) Use of fluorescently labeled DNA and a scanner for electrophoretic mobility shift assays. Biotechniques 30:504–6, 508

    PubMed  CAS  Google Scholar 

  54. Paulose M, Bennett B, Manning A et al (1998) Selective inhibition of TNF-alpha induced cell adhesion molecule gene expression by tanapox virus. Microb Pathog 25:33–41

    Article  PubMed  CAS  Google Scholar 

  55. Romashkova JA, Makarov SS (1999) NF-κB is a target of AKT in anti-apoptotic PDGF signaling. Nature 401:85–90

    Google Scholar 

  56. Rauch BH, Weber A-A, Braun M et al (2000) PDGF-induced AKT phosphorylation does not activate NF-κB in human vascular smooth muscle cells and fibroblasts. FEBS Lett 481:3–7

    Article  PubMed  CAS  Google Scholar 

  57. Li JJ, Westergaard C, Ghosh P et al (1997) Inhibitors of both nuclear factor-kappaB and activator protein-1 activation block the neoplastic transformation response. Cancer Res 57:3569–76

    PubMed  CAS  Google Scholar 

  58. Bian X, Opipari AWJ, Ratanaproeksa AB et al (2002) Constitutively active NF-κB is required for the survival of S-type neuroblastoma. J Biol Chem 277:42144–42150

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors would like to acknowledge Dr. John Geiser for critical reading of the manuscript and Dr. Todd Barkman for sequencing. This work was funded by grants from the National Institutes of Health and the Elsa U. Pardee Foundation.

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Correspondence to Bruce E. Bejcek.

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Smith, D., Shimamura, T., Barbera, S. et al. NF-κB controls growth of glioblastomas/astrocytomas. Mol Cell Biochem 307, 141–147 (2008). https://doi.org/10.1007/s11010-007-9593-4

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  • DOI: https://doi.org/10.1007/s11010-007-9593-4

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