Skip to main content

Advertisement

SpringerLink
Log in

Aberrant constitutive activation of nuclear factor κB in glioblastoma multiforme drives invasive phenotype

  • Lab. Investigation-human/animal tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Several recent studies have shown that aberrant constitutive activation of nuclear factor kappaB (NF-κB) is present in a variety of cancers including gliomas. NF-κB is known to play important roles in the physiological regulation of diverse cellular processes such as inflammation, growth and immunity. In contrast, aberrant activation of this latent transcription factor promotes cancer cell migration, invasion and resistance to chemotherapy. Here we show by electro-mobility shift assay (EMSA) and immuno-staining that constitutive NF-κB activation is present in various malignant glioma cell lines as well as in primary cultures derived from tumor tissue. This activation was not serum dependent and it led to high IL-8 gene transcription and protein production. Over-expression of an I-κB super-repressor (I-κB SR) transgene completely blocked constitutive NF-κB activation, nuclear localization and transcription of some but not all NF-κB regulated genes indicating that NF-κB signaling in glioma cells is I-κB dependent. Surprisingly, over-expression of IκBSR did not have any effect on the transcription levels of anti-apoptotic genes in these glioma cultures and cell lines. Down-regulation of NF-κB activation reduced invasion of glioma cells through matrigel. Collectively these data suggest that aberrant constitutive activation of NF-κB in glioblastoma cells promotes their invasive phenotype. Interruption of this aberrant NF-κB activity may help reduce the spread of this infiltrative tumor.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Sawaya R, Ligon BL, Bindal AK, Bindal RK, Hess KR (1996) Surgical treatment of metastatic brain tumors. J Neurooncol 27:269–277

    Article  PubMed  CAS  Google Scholar 

  2. Baldwin AS Jr (2001) Series introduction: the transcription factor NF-kappaB, human disease. J Clin Invest 107:3–6

    Article  PubMed  CAS  Google Scholar 

  3. Higgins KA, Perez JR, Coleman TA, Dorshkind K, McComas WA, Sarmiento UM, Rosen CA, Narayanan R (1993) Antisense inhibition of the p65 subunit of NF-kappa B blocks tumorigenicity and causes tumor regression. Proc Natl Acad Sci USA 90:9901–9915

    Article  PubMed  CAS  Google Scholar 

  4. Beg AA, Baltimore D (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274:782–784

    Article  PubMed  CAS  Google Scholar 

  5. Gilmore TD, Koedood M, Piffat KA, White DW (1996) Rel/NF-kappaB/IkappaB proteins and cancer. Oncogene 13:1367–1378

    PubMed  CAS  Google Scholar 

  6. Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM (1996) Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science 274:787–789

    Article  PubMed  Google Scholar 

  7. Wang CY, Mayo MW, Baldwin AS Jr (1996) TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 274:784–787

    Article  PubMed  CAS  Google Scholar 

  8. Duffey DC, Chen Z, Dong G, Ondrey FG, Wolf JS, Brown K, Siebenlist U, Van Waes C (1999) 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

    PubMed  CAS  Google Scholar 

  9. Yoshida A, Yoshida S, Ishibashi T, Kuwano M, Inomata H (1999) Suppression of retinal neovascularization by the NF-kappaB inhibitor pyrrolidine dithiocarbamate in mice. Invest Ophthalmol Vis Sci 40:1624–1629

    PubMed  CAS  Google Scholar 

  10. Huang S, DeGuzman A, Bucana CD, Fidler IJ (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 

  11. Aggarwal BB Nuclear factor-kappaB: the enemy within (2004) Cancer Cell 6:203–208

  12. Ritchie CK, Giordano A, Khalili K (2000) Integrin involvement in glioblastoma multiforme: possible regulation by NF-kappaB. J Cell Physiol 184:214–221

    Article  PubMed  CAS  Google Scholar 

  13. Bjorklund M, Koivunen E (2005) Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta 1755:37–69

    PubMed  Google Scholar 

  14. Griffin JD (2001) Leukemia stem cells and constitutive activation of NK-kappaB. Blood 6:203–208

    Google Scholar 

  15. Feinman R, Koury J, Thames M, Barlogie B, Epstein J, Siegel DS (1999) Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2. Blood 93:3044–3052

    PubMed  CAS  Google Scholar 

  16. Kordes U, Krappmann D, Heissmeyer V, Ludwig WD, Scheidereit C (2000) Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 14:399–402

    Article  PubMed  CAS  Google Scholar 

  17. Baron F, Turhan AG, Giron-Michel J, Azzarone B, Bentires-Alj M, Bours V, Bourhis JH, Chouaib S, Caignard A (2002) Leukemic target susceptibility to natural killer cytotoxicity: relationship with BCR-ABL expression. Blood 99:2107–2113

    Article  PubMed  CAS  Google Scholar 

  18. Palayoor ST, Youmell MY, Calderwood SK, Coleman CN, Price BD (1999) Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen. Oncogene 18:7389–7394

    Article  PubMed  CAS  Google Scholar 

  19. Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet RJ Jr, Sledge GW Jr (1997) Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol 17:3629–3639

    PubMed  CAS  Google Scholar 

  20. Bian X, Opipari AW Jr, Ratanaproeksa AB, Boitano AE, Lucas PC, Castle VP (2002) Constitutively active NFkappa B is required for the survival of S-type neuroblastoma. J Biol Chem 277:42144–42150

    Article  PubMed  CAS  Google Scholar 

  21. Nagai S, Washiyama K, Kurimoto M, Takaku A, Endo S, Kumanishi T (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 

  22. Gill JS, Zhu X, Moore MJ, Lu L, Yaszemski MJ, Windebank AJ (2002) Effects of NFkappaB decoy oligonucleotides released from biodegradable polymer microparticles on a glioblastoma cell line. Biomaterials 23:2773–2781

    Article  PubMed  CAS  Google Scholar 

  23. Hata N, Yoshimoto K, Yokoyama N, Mizoguchi M, Shono T, Guan Y, Tahira T, Kukita Y, Higasa K, Nagata S, Iwaki T, Sasaki T, Hayashi K (2006) Allelic losses of chromosome 10 in glioma tissues detected by quantitative single-strand conformation polymorphism analysis. Clin Chem 52:370–378

    Article  PubMed  CAS  Google Scholar 

  24. Sizemore N, Lerner N, Dombrowski N, Sakurai H, Stark GR (2002) Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappa B. J Biol Chem 277:3863–3869

    Article  PubMed  CAS  Google Scholar 

  25. Wolf S, Chen Z, Dong G, Sunwoo JB, Bancroft CC, Capo DE, Yeh NT, Mukaida N, Van Waes C (2001) IL (interleukin)-lalpha promotes nuclear factor-kappaB and AP-1-induced IL-8 expression, cell survival, and proliferation in head and neck squamous cell carcinomas. Clin Cancer Res 7(6):1812–1820

    PubMed  CAS  Google Scholar 

  26. Arlt A, Vorndamm J, Muerkoster S, Yu H, Schmidt WE, Folsch UR, Schafer H (2002) Autocrine production of interleukin 1beta confers constitutive nuclear factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines. Cancer Res 62:910–916

    PubMed  CAS  Google Scholar 

  27. Coward WR, Okayama Y, Sagara H, Wilson SJ, Holgate ST, Church MK (2002) NF-kappa B and TNF-alpha: a positive autocrine loop in human lung mast cells? J Immunol 169:5287–5293

    PubMed  Google Scholar 

  28. Lu T, Strak G (2004) Cytokine overexpression and constitutive NF-kappa B in cancer. Cell Cycle 3:1114–1117

    PubMed  CAS  Google Scholar 

  29. Wakabayashi K, Kambe F, Cao X, Murakami R, Mitsuyama H, Nagaya T, Saito K, Yoshida J, Seo H (2004) Inhibitory effects of cyclosporin A on calcium mobilization-dependent interleukin-8 expression and invasive potential of human glioblastoma U251MG cells. Oncogene 23:6924–6932

    Article  PubMed  CAS  Google Scholar 

  30. Mahe Y, Mukaida N, Kuno K, Akiyama M, Ikeda N, Matsushima K, Murakami S (1991) Hepatitis B virus X protein transactivates human interleukin-8 gene through acting on nuclear factor kB and CCAAT/enhancer-binding protein-like cis-elements. J Biol Chem 266:13759–13763

    PubMed  CAS  Google Scholar 

  31. Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S (1993) Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci USA 90:10193–10197

    Article  PubMed  CAS  Google Scholar 

  32. Lefranc F, Brotchi J, Kiss R (2005) Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J Clin Oncol 23:2411–2422

    Article  PubMed  CAS  Google Scholar 

  33. Rao JS (2003) Molecular mechanisms of glioma invasiveness: the role of proteases. Nat Rev Cancer 3:489–501

    Article  PubMed  CAS  Google Scholar 

  34. Brat DJ, Bellail AC, Van Meir EG (2005) The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-oncol 7:122–133

    Article  PubMed  CAS  Google Scholar 

  35. Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ (2001) Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 20:4188–4197

    Article  PubMed  CAS  Google Scholar 

  36. Fujioka S, Sclabas GM, Schmidt C, Frederick WA, Dong QG, Abbruzzese JL, Evans DB, Baker C, Chiao PJ (2003) Function of nuclear factor kappaB in pancreatic cancer metastasis. Clin Cancer Res 9:346–354

    PubMed  CAS  Google Scholar 

  37. Watanabe H, Iwase M, Ohashi M, Nagumo M (2002) Role of interleukin-8 secreted from human oral squamous cell carcinoma cell lines. Oral Oncol 38:670–679

    Article  PubMed  CAS  Google Scholar 

  38. Lin Y, Huang R, Chen L, Li S, Shi Q, Jordan C, Huang RP (2004) Identification of interleukin-8 as estrogen receptor-regulated factor involved in breast cancer invasion and angiogenesis by protein arrays. Int J Cancer 109:507–515

    Article  PubMed  CAS  Google Scholar 

  39. Robe PA, Bentires-Alj M, Bonif M, Rogister B, Deprez M, Haddada H, Khac MT, Jolois O, Erkmen K, Merville MP, Black PM, Bours V (2004) In vitro and in vivo activity of the nuclear factor-kappaB inhibitor sulfasalazine in human glioblastomas. Clin Cancer Res 10:5595–5603

    Article  PubMed  CAS  Google Scholar 

  40. Lamszus K, Brockmann MA, Eckerich C, Bohlen P, May C, Mangold U, Fillbrandt R, Westphal M (2005) Inhibition of glioblastoma angiogenesis and invasion by combined treatments directed against vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and vascular endothelial-cadherin. Clin Cancer Res 11(13):4934–4940

    Article  PubMed  CAS  Google Scholar 

  41. Hu B, Jarzynka MJ, Guo P, Imanishi Y, Schlaepfer DD, Cheng SY (2006) Angiopoietin 2 induces glioma cell invasion by stimulating matrix metalloprotease 2 expression through the alphavbeta1 integrin and focal adhesion kinase signaling pathway. Cancer Res 66(2):775–783

    Article  PubMed  CAS  Google Scholar 

  42. Mayes DA, Hu Y, Teng Y, Siegel E, Wu X, Panda K, Tan F, Yung WK, Zhou YH (2006) PAX6 suppresses the invasiveness of glioblastoma cells and the expression of the matrix metalloproteinase-2 gene. Cancer Res 66(20):9809–9817

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Brain Tumor Institute and Taussig Cancer Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Baisakhi Raychaudhuri, Yulong Han & Michael A. Vogelbaum

  2. Department of Molecular Genetics, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Tao Lu

Authors
  1. Baisakhi Raychaudhuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yulong Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tao Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael A. Vogelbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael A. Vogelbaum.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Raychaudhuri, B., Han, Y., Lu, T. et al. Aberrant constitutive activation of nuclear factor κB in glioblastoma multiforme drives invasive phenotype. J Neurooncol 85, 39–47 (2007). https://doi.org/10.1007/s11060-007-9390-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-007-9390-7

Keywords

Search

Navigation