Skip to main content
SpringerLink
Log in

Increased intracellular cyclic AMP levels suppress the mitogenic responses of human astrocytoma cells to growth factors

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

Summary

It has been shown that the intracellular cAMP levels were decreased in human malignant astrocytomas. On the other hand, various growth factors and their receptors were found to be overexpressed in these tumors. It is therefore intriguing as to whether there is interplay between the two phenomena in the modulation of the astrocytoma cell growth. In a basal medium consisting of 75% DMEM, 25% Ham's F-12 supplemented with 2% FBS, we show that the mitogenic effects of platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) on human astrocytoma cells were suppressed by dibutyryl-cAMP. Dibutyryl-cAMP alone neither potentiated nor inhibited the tumor cell growth. Further studies show that PDGF-induced receptor autophosphorylation in human astrocytoma cells is suppressed by increased intracellular cAMP levels as measured by immunoprecipitation with anti-PDGF receptor and antiphosphotyrosine antibodies. Our results indicate that there is antagonistic interplay between the receptor tyrosine kinase pathway and cAMP-dependent protein kinase pathway in the control of the malignantly transformed glial cells. A reduced cAMP level seen in many human astrocytoma cells may favor their response to growth factor mitogenesis.

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. Carpenter G: Properties of the receptor for epidermal growth factor. Cell 37: 357–358, 1984

    Google Scholar 

  2. Rifkin DB, Moscatelli D: Recent developments in the cell biology of basic fibroblast growth factor. J Cell Biol 109: 1–6, 1989

    Google Scholar 

  3. Schlessinger J, Ullrich A: Growth factor signaling by receptor tyrosine kinases. Neuron 9: 383–391, 1992

    Google Scholar 

  4. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R, Soltoff S: Oncogenes and signal transduction. Cell 64: 281–302, 1991

    Google Scholar 

  5. Posada J, Cooper JA: Molecular signal integration. Mol Cell Biol 3: 583–592, 1992

    Google Scholar 

  6. Pawson T, Gish GD: SH2 and SH3 domains: from structure to function. Cell 71: 359–362, 1992

    Google Scholar 

  7. Wen Y, Anwer K, Sing SP, Sanborn BM: Protein kinase-A inhibits phospholipase-C activity and alters protein phosphorylation in rat myometrial plasma membranes. Endocrinology 131: 1377–1382, 1992

    Google Scholar 

  8. Whitman M, Cantley L: Phosphoinositide metabolism and the control of cell proliferation. Biophys Acta 948: 327–344, 1988

    Google Scholar 

  9. Diamond L, O'Brien S, Shimizu Y: Growth stimulation of human diploid fibroblasts by the tumor promoter, 12-o-tetradecanoyl-phorbol-13-acetate. Int J Cancer 13: 721–730, 1974

    Google Scholar 

  10. Pollack IF, Randall MS, Kristofik MP, Kelly RH, Selker RG, Vertosick FT: Response of malignant glioma cell lines to activation and inhibition of protein kinase C-mediated pathways. J Neurosurg 73: 98–105, 1990

    Google Scholar 

  11. Toullec D, Pianetti P, Coste H, Bellevergue P, Grand-Perret T, Ajakane M, Baudet V, Boissin P, Boursier E, Loriolle F, Dukame L, Charon D, Kirilovsky J: The bisindolymaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem 266: 15771–15781, 1991

    Google Scholar 

  12. Maeda Y, Terada Y, Nonoguchi H, Knepper MA: Hormone and autacoid regulation of cAMP production in rat IMCD subsegments. Am J Physiol 263: F319–327, 1992

    Google Scholar 

  13. Zohar M, Salomon Y: Melanocortins stimulate proliferation and induce morphological changes in cultured rat astrocytes by distinct transducing mechanisms. Brain Res 576: 49–58, 1992

    Google Scholar 

  14. Dumont JE, Jauniaux JC, Roger PP: The cyclic AMP-mediated stimulation of cell proliferation. Trend Biochem Sci 14: 67–71, 1989

    Google Scholar 

  15. Landis CA, Masters SB, Spada A, Pace AM, Bourne HR, Vallar L: GTPase inhibiting mutations activate the α chain of Gs and stimulate adenylyl cyclase in human pituitary tumors. Nature 340: 692–696, 1989

    Google Scholar 

  16. Suarez HG, du Villard JA, Caillou B, Schmberg M, Parmentier C, Monier R: gsp mutations in human thyroid tumors. Oncogene 6: 677–679, 1991

    Google Scholar 

  17. Chen JK, Yao LL, Jenq CB: Mitogenic response of rat Schwann cells to fibroblast growth factors is potentiated by increased intracellular cyclic AMP levels. J Neurosci Res 30: 321–327, 1991

    Google Scholar 

  18. Davis JB, Stroobant P: Platelet-derived growth factors and fibroblast growth factors are mitogens for rat Schwann cells. J Cell Biol 110: 1353–1360, 1990

    Google Scholar 

  19. Bell JD, Duxton ILO, Brunton LL: Enhancement of adenylate cyclase activity in S49 lymphoma cels by phorbol esters. Putative effect of C kinase on alpha s-GTP-catalytic subunit interaction. J Biol Chem 260: 2625–2628, 1985

    Google Scholar 

  20. Dascal N, Lotan I, Gillo B, Lester HA, Lass Y: Acetylcholine and phorbol esters inhibit potassium currents evoked by adenosine and cAMP in Xenopus oocytes. Proc Natl Acad Sci USA 82: 6001–6005, 1985

    Google Scholar 

  21. Rebois RV, Patel J: Phorbol ester causes desensitization of gonadotropin-responsive adenylate cyclase in a murine Ledig tumor cell line. J Biol Chem 260: 8026–8031, 1985

    Google Scholar 

  22. Nishizuka Y: Studies and perspectives of protein kinase C. Science 233: 305–312, 1986

    Google Scholar 

  23. Heldin NE, Paulsson Y, Forsberg K, Heldin CH, Westermark B: Induction of cyclic AMP synthesis by forskolin is followed by a reduction in the expression of c-myc messenger RNA and inhibition of3H-thymidine incorporation in human fibroblasts. J Cell Physiol 138: 17–23, 1989

    Google Scholar 

  24. Daniel TO, Gibbs VC, Milfay DF, Williams LT: Agents that increase cAMP accumulation block endothelial c-sis induction by thrombin and transforming growth factor-beta. J Biol Chem 262: 11893–11896, 1987

    Google Scholar 

  25. Rozengurt E, Stroobant P, Waterfield MD, Deuel TF, Keehan M: Platelet-derived growth factor elicits cycle AMP accumulation in Swiss 3T3 cells: role of prostaglandin production. Cell 34: 265–272, 1983

    Google Scholar 

  26. Furman MA, Shulman K: Cyclic AMP and adenyl cyclase in brain tumors. J Neurosurg 46: 477–483, 1977

    Google Scholar 

  27. Akutsu Y, Aida T, Nakazawa S, Asano G: Localization of acidic and basic fibroblast growth factor mRNA in human brain tumors. Jpn J Cancer Res 82: 1022–1027, 1991

    Google Scholar 

  28. Fleming TP, Saxena A, Clark WC, Robertson JT, Olfdield EH, Aronson SA, Ali IU: Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res 52: 4550–4553, 1992

    Google Scholar 

  29. Hermansson M, Nister M, Betsholtz C, Heldin CH, Westermark B, Funa K: Endothelial cell hyperplasia in human glioblastoma: co-expression of mRNA for platelet-derived growth factor (PDGF) B chain and PDGF receptor suggests autocrine growth stimulation. Proc Natl Acad Sci USA 85: 7748–7752, 1988

    Google Scholar 

  30. Libermann TA, Nusbaum HR, Rozon N, Kris R, Lax I, Soreq H, Wittle N, Waterfield MD, Ullrich A, Schlessinger JS: Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumors of glial origin. Nature 313: 144–147, 1985

    Google Scholar 

  31. Steck PA, Lee P, Hung MC, Yung WK: Expression of an altered epidermal growth factor receptor by human glioblastoma cells. Cancer Res 48: 5433–5439, 1988

    Google Scholar 

  32. Stefanik DF, Rizkalla LR, Soi A, Goldblatt SA, Rizkalla WM: Acadic and basic fibroblast growth factors are present in glioblastoma multiforme. Cancer Res 51: 5760–5765, 1991

    Google Scholar 

  33. Zulch KJ: Histologie typing of tumours of the central nervous system. Geneve: WHO, 1979

    Google Scholar 

  34. Chen J-K, Li S-R, Tsai RJ-F: Cyclic AMP-induced inhibition of collagen lattice contraction by fibroblasts may be attenuated by both cyclic AMP dependent and independent mechanisms. J Cell Physiol 155: 8–13, 1993

    Google Scholar 

  35. Lim R, Mitsumobu K: Effect of dibutyryl cyclic AMP on nucleic acid and protein synthesis in neuronal and glial tumor cells. Life Sci 11: 1063–1070, 1972

    Google Scholar 

  36. Fu X-Y, Zhang J-J: Transcription factor p91 interacts with the epidermal growth factor receptor and mediates activation of the c-fos gene promoter. Cell 74: 1135–1145, 1993

    Google Scholar 

  37. Couldwell WT, Uhm JH, Antel JR, Yong VW: Enhanced protein kinase C activity correlates with the growth rate of malignant gliomain vitro. Neurosurgery 29: 880–887, 1991

    Google Scholar 

  38. Gouldwell WT, Antel JP, Yong VW: Protein kinase C activity correlates with the growth of malignant gliomas: part II effects of glioma mitogens and modulators of protein kinase C. Neurosurgery 31: 717–724, 1992

    Google Scholar 

  39. Carpenter CL, Cantley LC: Phosphoinositide kinases. Biochemistry 29: 1147–1156, 1990

    Google Scholar 

  40. Stephens LR, Hughes KT, Irvine RF: Pathway of phosphatidylinositol (3,4,5)-trisphosphate synthesis in activated neutrophils. Nature 351: 33–39, 1991

    Google Scholar 

  41. Jackson TR, Stephens LR, Hawkins RT: Receptor specificity of growth factor-stimulated synthesis of 3-phosphorylated inositol lipids in Swiss 3T3 cells. J Biol Chem 267: 16627–16636, 1992

    Google Scholar 

  42. Nakanishi H, Brewer KA, Exon JH: Activation of the ζ isozyme of protein kinase C by phosphatidylinositol 3,4,5-Trisphosphate. J Biol Chem 268: 13–16, 1993

    Google Scholar 

  43. Berra E, Diaz-Meco MT, Dominguez I, Municio MM, Sanz L, Lozano J, Chapkin RS, Moscat J: Protein kinase C ζ isoform is critical for mitogenic signal transduction. Cell 74: 555–563, 1993

    Google Scholar 

  44. Edstrom A, Kanje M, Walum E: Effects of dibutyryl cyclic AMP and prostaglandin E1 on cultured human glioma cells. Exp Cell Res 85: 217–223, 1974

    Google Scholar 

  45. Lim R, Mitsunobu K: Effect of dibutyryl cyclic AMP on nucleic acid and protein synthesis in neuronal and glial tumor cells. Life Sci 11: 1063–1070, 1972

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Chang Gung Memorial Hospital, Taiwan

    Chon-Haw Tsai

  2. Department of Physiology, Chang Gang College of Medicine and Technology, Kweishan, Taoyuan, Taiwan

    Li-Man Hung, Ho-Ping Cheng & Jan-Kan Chen

Authors
  1. Chon-Haw Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li-Man Hung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ho-Ping Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jan-Kan Chen
    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

Tsai, CH., Hung, LM., Cheng, HP. et al. Increased intracellular cyclic AMP levels suppress the mitogenic responses of human astrocytoma cells to growth factors. J Neuro-Oncol 23, 41–52 (1995). https://doi.org/10.1007/BF01058458

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01058458

Key words

Search

Navigation