Skip to main content
SpringerLink
Log in

Interferon-β inhibits proliferation and progression through S phase of the cell cycle in five glioma cell lines

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

Summary

The growth inhibitory effect of IFN-β was evaluated in 5 human glioma cell lines (AO2V4, GJC, GJR, NN and NNR) and in normal astrocyte cultures (SC and TM). All 5 glioma cell lines showed an anti-proliferative response to IFN-β whereas normal glial cells were non-responsive. IFN-β at 10, 100 and 500 U/ml lead to a 30%,70% and 80% relative decrease in cell number after 12 days, respectively in AO2V4 cells. GJC and GJR cell lines also responded significantly to the lowest concentration of IFN-β tested and at 500 U/ml the relative cell number decreased 55%. The NN and NNR cells were the least responsive to IFN-β with maximum growth inhibition of 30% at 500 U IFN-β/ml. Following treatment with IFN-β, AO2V4, GJC, GJR and normal astrocytes all expressed mRNA encoding the anti-viral protein, 2-5A synthetase demonstrating that IFN-β bound to receptors on all four cell lines and activated signal transduction pathways required for induction of an anti-viral protein. A determination of the relative number of viable cells showed that none of these cells exhibited a significant decrease in cell viability. Since the antiproliferative response to IFN-β was not primarily due to cell death, the effect of IFN-β on cell cycle progression was evaluated by flow cytometry. All treated glioma cell lines showed a relative increase in proportion of cells in S phase. AO2V4 cells had a 50%–80% increase in the percentage of cells in S phase, whereas GJC, GJR and NNR had percentage increases of 20%–40%. IFN-β treatment of normal astrocytes did not significantly alter their cell cycle profile. These data suggest that IFN-β exerts its antiproliferative effect on glioma cells by arresting the ordered progression through S phase or decreasing entry into G2/M phase of the cell cycle.

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. Janus TJ, Kyritsis AP, Forman AD, Levin VA: Biology and treatment of gliomas. Annals of Oncol 3: 423–433, 1992

    Google Scholar 

  2. Shapiro JR, Yung WKA, Shapiro WR: Isolation, karyotype, and clonal growth of heterogeneous subpopulations of human malignant gliomas. Cane Res 41: 2349–2359, 1981

    Google Scholar 

  3. Hirakawa K, Ueda S, Nakagawa Y, Suzuki K, Fukuma S, Kita M, Imanishi J, Kishida T: Effect of human leukocyte interferon on malignant brain tumors. Cancer 51: 1976–1981, 1983

    Google Scholar 

  4. Yung WK, Castellanos AM, Van Tassel P, Moser RP, Marcus SG: A pilot study of recombinant interferon beta (IFN-beta ser) in patients with recurrent glioma. J Neuro-Oncol 9: 2934, 1990

    Google Scholar 

  5. Atanasiu P, Chany C: Action d'un interferon provenant de cellules malignes sur l'infection expérimentale du Hamster nouveau-né par le virus du polyome. C R Acad Sci (Paris) 251:1687–1689, 1960

    Google Scholar 

  6. Stuart II WE: The Interferon System. Springer-Verlag, New York, 1979, pp 292–303

    Google Scholar 

  7. Borden EC: Progress towards therapeutic application of interferons. Cancer 54: 2770–2776, 1984

    Google Scholar 

  8. Nelson BE, Borden EC: Interferons: biological and clinical effects. Semin Surg Oncol 5: 391–401, 1989

    Google Scholar 

  9. Dianzani F: Biological basis for therapy and for side effects. In: Baron S, Coppenhaver DH, Dianzani F, Fleischman Jr WR, Hughes Jr TK, Klimpel GR, Niesel DW, Stanton GJ, Tyring SK (eds) Interferon: Principles and Medical Applications. The University of Texas Medical Branch at Galveston, Galveston, 1992, pp 409–416

    Google Scholar 

  10. Lengyel P: Tumor-suppressor gene: news about the interferon connection. Proc Natl Acad Sci USA 90: 5893–5895, 1993

    Google Scholar 

  11. Borden EC, Waalen J, Schreiber R, Williams B: Response and resistance to interferons and interacting cytokines. J Natl Cancer Inst 87: 257–264, 1995

    Google Scholar 

  12. Floyd-Smith G, Lengyel P: Mechanisms of interferon action: characteristics of RNase L, the (2′-5′) (A)-n-dependent endoribonuclease. In: Grunberg-Manago M, Safer B (eds) Interaction of Translational and Transcriptional Controls in the Regulation of Gene Expression. Elsevier Publ Co, North Holland, 1982, pp 417–433

    Google Scholar 

  13. Lin SL, Kikuchi T, Pledger WJ, Tamm I: Interferon inhibits the establishment of competence in G0/S-phase transition. Science 233: 356–359, 1986

    Google Scholar 

  14. Einat M, Resnitzky D, Kimchi A: Close link between reduction of c-myc expression by interferon and G0/G1 arrest. Nature 313: 597–600, 1985

    Google Scholar 

  15. Numa Y, Kawamoto K, Sakai M, Matsumura H: Flow cytometric analysis of antineoplastic effects of interferon-α, -β and -7 labelled with fluorescein isothiocyanate on cultured brain tumors. J Neuro-Oncol 11: 225–234, 1991

    Google Scholar 

  16. Kimchi A: Cytokine triggered molecular pathways that control cell cycle arrest. J Cell Biochem 50: 1–9, 1992

    Google Scholar 

  17. Pape KA, Floyd-Smith G: Effects of interferon-β on Daudi cells and on small cell lung carcinoma cells which over-express the c-myc oncogene. Anticancer Res 9:1737–1742, 1989

    Google Scholar 

  18. Pantazis P, Pelicci PG, Dalla-Favera R, Antoniades HN: Synthesis and secretion of proteins resembling platelet-derived growth factor by human gliobastoma and fibrosarcoma cells in culture. Proc Nall Acad Sci USA 82: 2404–2408, 1985

    Google Scholar 

  19. Shapiro JR, Mehta BM, Ebrahim SAD, Scheck AC, Moots RL, Fiola MR: Tumor heterogeneity and intrinsically chemoresistant subpopulations in freshly resected human malignant gliomas. In: Sudilovsky O, Pilot HC, Liotta LA (eds) Boundaries between Promotion and Progression during Carcinogenesis. Plenum Publ Corp, New York, 1991, pp 243–262

    Google Scholar 

  20. Berens ME, Rief MD, Loo MA, Giese A: The role of extracellular matrix in human astrocytoma migration and proliferation studied in a microliter scale assay. Clin Exp Metastasis 12: 405–415, 1994

    Google Scholar 

  21. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65: 55–63, 1985

    Google Scholar 

  22. Burghardt RC, Barhoumi R, Doolittle DJ, Phillips TD: Application of cellular fluorescence imaging for in vitro toxicology testing. In: Hayes AW (ed.) Principles and Methods of Toxicology, 3rd ed. Raven Press, New York, 1994, pp 1231–1258

    Google Scholar 

  23. Coons SW, Johnson PC: Regional heterogeneity in the DNA content of human gliomas. Cancer 72: 3052–3060, 1993

    Google Scholar 

  24. Chomezynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159, 1987

    Article  CAS  PubMed  Google Scholar 

  25. Puissant C, Houdebine LM: An improvement of the single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. BioTech 8: 148–149, 1990

    Google Scholar 

  26. Henderson GS, Conary JT, Davidson JM, Stewart SJ, House FS, McCurley TL: A reliable method for northern blot analysis using synthetic oligonucleotide probes. BioTech 10:190–197, 1991

    Google Scholar 

  27. Shih N-Y, Floyd-Smith G: Invariant chain (CD74) gene regulation: Enhanced expression associated with activation of protein kinase Cδ in a murine B lymphoma cell line. Mol Immunol 32:643–650, 1995

    Google Scholar 

  28. Benech P, Mory Y, Revel M, Chebath J: Structure of two forms of the interferon-induced (2′-5′) oligo A synthetase of human cells based on cDNAs and gene sequences. EMBO J 4:2249–2256, 1985

    Google Scholar 

  29. Ercolani L, Florence B, Denaro M, Alexander M: Isolation and complete sequence of a functional human glyceraldehyde-3-phosphate dehydrogenase gene. J Biol Chem 263: 15335–15341, 1988

    Google Scholar 

  30. Deng GR, Wu R: Terminal transferase: use in the tailing of DNA and for in vitro mutagenesis. Meth Enzymol 100: 96–116, 1983

    Google Scholar 

  31. Nikkhah G, Torn JC, Hoffmann O, Kraemer H-P, Darling JL, Schonmayr R, Schschenmayr W: The MTT assay for chemosensitivity testing of human tumors of the central nervous system. Part I: Evaluation of test-specific variables. J Neuro-Oncol 13:1–11, 1992

    Google Scholar 

  32. Bradley NJ, Darling JL, Oktar N, Bloom HJG, Savis AJS: The failure of human leukocyte interferon to influence the growth of human glioma cell populations: In vitro and in vivo studies. Br J Cancer 48: 819–825, 1983

    Google Scholar 

  33. Cook AW, Carter WA, Nidzgorsiki F, Akhtar L: Human brain tumor-derived cell lines: Growth rate reduced by human fibroblast interferon. Science 219: 881–883, 1983

    Google Scholar 

  34. Rosenblum MG, Yung WKA, Kelleher PJ, Ruzicka F, Steck PA, Borden EC: Growth inhibitory effects of interferon-β but not interferon-α on human glioma cells: Correlation of receptor binding, 2′-5′-oligoadenylate synthetase and protein kinase activity. J Interferon Res 10: 141–151, 1990

    Google Scholar 

  35. Pestka S, Langer JA, Zoon KC, Samuel CE: Interferons and their actions. Annu Rev Biochem 56: 727–777, 1987

    Google Scholar 

  36. Munoz-Fernandez MA, Armas-Portela R, Diaz-Nido J, Alonso JL, Fresno M, Avila J: Differential effects of tumor necrosis factor on the growth and differentiation of neuroblastoma and glioma cells. Exp Cell Res 194: 161–164, 1991

    Google Scholar 

  37. Tejada-Berens T, Yong VW. The astrocyte mitogen, tumor necrosis factor-alpha, inhibits the proliferative effects of more potent adult human astrocyte mitogens, gamma-interferon and activated T-lymphocyte supernatant. Brain Res 653: 297–304, 1994

    Google Scholar 

  38. Alfinito F, Lamberti A, Capobianchi MR, Nigro M, De Rosa G, Tassone P, Turco MC, Dianzani F, Venuta S: T cell growth-promoting activity of interferon-gamma. Mitogenic effect of the recombinant cytokine on cells from a human T-chronic lymphocytic leukemia. Leukemia 8: 1294–1300, 1994

    Google Scholar 

  39. Vollmer S, Menssen A, Trommler P, Schendel D, Prinz JC: T lymphocytes derived from skin lesions of patients with psoriasis vulgaris express a novel cytokine pattern that is distinct from that of T helper type 1 and T helper type 2 cells. Eur J Immunol 24: 2377–2382, 1994

    Google Scholar 

  40. Darnell JE, Kerr IM, Stark GR: Jak-STAT pathways and transcriptional activation in responses to IFNs and other extracellular signaling proteins. Science 264:1415–1421, 1994

    Google Scholar 

  41. Uzé G, Lutfalla G, Gresser I: Genetic transfer of a functional human interferon a receptor into mouse cells: cloning and expression of its cDNA. Cell 60: 225–234, 1990

    Google Scholar 

  42. Novick D, Cohen B, Rubinstein M: The human interferon α/β receptor: characterization and molecular cloning. Cell 77: 391–400, 1994

    Google Scholar 

  43. Yates JA, Stephens RE, Elder PJ, Markowitz PL, Rice JM: Effects of interferon and gangliosides on growth of cultured human glioma and fetal brain cells. Cancer Res 45: 1033–1039, 1985

    Google Scholar 

  44. Watanabe-Fukunaga R, Brannan CI, Itoh N, Yonehara S, Copeland NG, Jenkins NA, Nagata S: The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol 148: 1274–1279, 1992

    CAS  PubMed  Google Scholar 

  45. Yoshida J, Mizuno M, Yagi K: Cytotoxicity of human betainterferon produced in human glioma cells permanently transfected with its gene by means of liposomes. Biochem Int 28: 1055–1061, 1992

    Google Scholar 

  46. Sherr CJ: G, phase progression: cycling on cue. Cell 79: 551–555, 1994

    Google Scholar 

  47. Nurse P: Ordering S phase and M phase in the cell cycle. Cell 79: 547–550, 1994

    Google Scholar 

  48. King RW Jackson PK, Kirschner M: Mitosis in transition. Cell 79: 563–571, 1994

    Google Scholar 

  49. Harada H, Kitagawa M, Tanaka N, Yamamoto H, Harada K, Ishihara M, Taniguchi T: Anti-oncogenic and oncogenic potentials of interferon regulatory factors-1 and -2. Science 259: 971–974, 1993

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Zoology, Arizona State University, 85208-1501, Tempe, Arizona, USA

    Judith I. Garrison, Sherri Treasurywala & Georgia Floyd-Smith

  2. Neuro-Oncology Research Laboratory, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, 85013-4496, Phoenix, AZ, USA

    Michael E. Berens & Joan Rankin Shapiro

Authors
  1. Judith I. Garrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael E. Berens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joan Rankin Shapiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sherri Treasurywala
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Georgia Floyd-Smith
    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

Garrison, J.I., Berens, M.E., Shapiro, J.R. et al. Interferon-β inhibits proliferation and progression through S phase of the cell cycle in five glioma cell lines. J Neuro-Oncol 30, 213–223 (1996). https://doi.org/10.1007/BF00177272

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00177272

Key words

Search

Navigation