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The mechanism of growth-regulation of glioma cells by trapidil

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Trapidil is a PDGF antagonist that can inhibit the proliferation of the PDGF-producing glioma cells, U251MG. As the mechanism of growth-regulation by trapidil remains unclear, we studied its effect on the growth of U251MG cells. We performed a cell cycle analysis and examined the intracellular transduction pathway and oncogene expression in serum-stimulated glioma cells with or without trapidil.

After the serum starvation for 3 days, glioma cell proliferation was stimulated by the addition of serum. Cell cycle analysis showed that cell cycle perturbations induced by trapidil included a decreased transition rate from G0-G1 to S phase, suggesting that some metabolic event is required for progress through the G0-G1 phase and that this event is sensitive to trapidil. Internal signal transduction mechanisms are central in the molecular control of cell growth. One such regulator is the protein kinase C(PKC) system and the c-fos gene is likely to be a direct target of intracellular signal transduction pathways. Therefore, we hypothesize that the intracellular PKC activity and c-fos expression of the trapidil-treated cells are suppressed. We posit that trapidil affects the intracellular signal transduction pathway PKC activity and c-fos expression in cells stimulated with serum containing growth factors.

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  1. 1.

    Nister M, Libermann TA, Betzholtz C, Pettersson M, Claesson-Welch L, Heldin CH, Schlessinger J, Westermmark B: Expression of messenger RNAs for platelet derived growth factor and transforming growth factor alpha and their receptors in human malignant glioma cell lines. Cancer Res 48: 3910–3918, 1988

  2. 2.

    Hermansson M, Nister M, Betsholtz C, Heldin CH, Westermark B, Funa K: Endothelial cell hyperplasia in human glioblastoma: coexpression of mRNA for platelet-derived growth factor (PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. Proc Natl Acad Sci USA 85: 7745–7752, 1988

  3. 3.

    Kuratsu J, Estes JE, Yokota S, Mahaley MS Jr, Gillespie GY: Growth factors derived from a human malignant glioma cell line, U251MG. J Neurooncol 7: 225–235, 1989

  4. 4.

    Kuratsu J, Ushio Y: Antiproliferative effect of trapidil, a platelet-derived growth factor antagonist, on a glioma cell linein vitro. J Neurosurg 73: 436–440, 1990

  5. 5.

    Kuratsu J, Takaki S, Mihara Y, Kochi M, Ushio Y: Antiproliferative effect of trapidil on a PDGF-producing glioma cell linein vivo. In: Tabuchi K (ed) Biological Aspects of Brain Tumors. Springer-Verlag, pp 469–473, 1990

  6. 6.

    Kuratsu J, Mihara Y, Takaki S, Ushio Y: Differentiation of glioma cells by a PDGF-anatagonist. Int J Oncol 1: 25–29, 1992

  7. 7.

    Trauche D, Robin P, Robillard O, Sassone-Corsi P, Harel-Bellan A: c-fos transcriptional activation by IL-2 in mouse CTL-L2 cells is mediated through two distinct signal transduction pathways converging on the same enhancer element. J Immunol 147: 2398–2403, 1991

  8. 8.

    Greenberg ME, Ziff EB: Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature 311: 433–438, 1984

  9. 9.

    Miller AD, Curran T, Verma I: c-fos protein can induce cellular transformation: a novel mechanism of activation of a cellular oncogene. Cell 36: 51–60, 1984

  10. 10.

    Kruijer W, Cooper JA, Hunter T, Verma IM: Platelet-derived growth factor induces rapid but transients expression of the c-fos gene and protein. Nature (London) 312: 711–716, 1984

  11. 11.

    Chirgwin JM, Przybyla AE, MacDonald RJ,et al.: Isolation of biologically active ribonucleic acid from sources enriched in ribonucleases. Biochemistry 18: 5294–5299, 1979

  12. 12.

    Todo T, Adams EF, Fahlbusch: Inhibitory effect of trapidil on human meningioma cells proliferation via interruption of autocrine growth stimulation. J Neurosurg 78: 463–469, 1993

  13. 13.

    Pardee AB, Dubrow R, Hamlin JL, Kletzien RF: Animal cell cycle. Ann Rev Biochem 47: 715–750, 1978

  14. 14.

    Stiles CD, Capone GT, Scher CD, Antoniades HN, Van Wyk JJ, Pledger WJ: Dual control of cell growth by somatomedins and platelet-derived growth factor. Proc Natl Acad Sci USA 76: 1279–1283, 1979

  15. 15.

    Todaro GJ, Lazar GK, Green H: The initiation of cell devision in a contact-inhibited mammalian cell line. J Cell Comp Physiol 66: 325–334, 1965

  16. 16.

    Pledger WJ, Stiles CD, Antoniades HN, Scher CD: Induction of DNA synthesis in BALB/c 3T3 cells by serum components. Reevaluation of the commitment process. Proc Natl Acad Sci USA 74: 4481–4485, 1977

  17. 17.

    Pledger WJ, Stiles CD, Antoniades HN, Scher CD: An ordered sequence of events is required before BALB/c 3T3 cells become committed to DNA synthesis. Proc Natl Acad Sci USA 75: 2839–2843, 1978

  18. 18.

    Antoniades HN, Scher CD, Stiles C: Platelet-derived growth factor. Proc Natl Acad Sci USA 76: 1809–1813, 1979

  19. 19.

    Deuel TF, Huang JS, Proffit RT, Baenzinger JU, Chang D, Kennedy BB: Human platelet-derived growth factor. Purificatin and resolution into two active protein fractions. J Biol Chem 256: 8896–8899, 1981

  20. 20.

    Heldin CH, Westermark B, Wasterson A: Platelet-derived growth factor: purification and partial characterization. Proc Natl Acad Sci USA 76: 3722–3726, 1979

  21. 21.

    Raines EW, Ross R: Platelet-derived growth factor. High yield purification and evidence for multiple forms. J Biol Chem 257: 5154–5160, 1982

  22. 22.

    Glenn K, Bowen-Pope DF, Ross R: Platelet-derived growth factor. Identification of platelet derived growth factor receptor by affinity labeling. J Biol Chem 257: 5172–5176, 1982

  23. 23.

    Ek B, Heldin CH: Characterization of a tyrosine-specific kinase activity in human fibroblast membranes stimulated by platelet-derived growth factor. J Biol Chem 257: 10486–10492, 1982

  24. 24.

    Westermark B, Ek B, Heldin CH: Stimulation of tyrosinespecific phosphorylation by platelet-derived growth factor. Nature 295: 419–420, 1982

  25. 25.

    Nishimura J, Huang JS, Deuel TF: Platelet-derived growth factor stimulates tyrosine-specific protein kinase activity in swiss mouse 3T3 cell membranes. Proc Natl Acad Sci USA 79: 4303–4307, 1982

  26. 26.

    Subramanian M, Schmidt LJ, Crutchfield III CE, Getz MJ: Negative regulation of serum-responsive enhancer elements. Nature 340: 64–66, 1989

  27. 27.

    Tresiman R: Transient accumulation of c-fos RNA following serum stimulation requires a conserved 5' element and c-fos 3′ sequences Cell 42: 889–902, 1985

  28. 28.

    Couldwell WT, Antel JP, Apuzzo MLJ: Inhibition of growth of established human glioma cell lines by modulators of the protein kinase-C system. J Neurosurg 73: 594–600, 1990

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Correspondence to Jun-ichi Kuratsu.

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Kuratsu, J., Sato, K., Saitoh, Y. et al. The mechanism of growth-regulation of glioma cells by trapidil. J Neuro-Oncol 23, 201–206 (1995).

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Key words

  • c-fos
  • fluorocytometry
  • glioma
  • platelet-derived growth factor
  • protein kinase C
  • trapidil