Skip to main content
SpringerLink
Log in

The Different Calcium Requirements of the Mitogenic Effects Elicited in Primary Neonatal Rat Hepatocytes by the Diterpene Phorbol Esters 12-O-Tetradecanoylphorbol-13-Acetate and Sapintoxin A

  • Chapter
Chemical Carcinogenesis 2

  • 70 Accesses

Abstract

A single exposure to a wide range of concentrations (10−13−10−5 mol/L) of the powerful, complete tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulated 4-day-old primary neonatal rat hepatocytes to synthesize new DNA and to divide within 24 hours independently on the actual (either high [1.8 mmol/L] or low [0.01 mmol/L]) concentration of calcium (Ca2+) in the surrounding HiWoBa2000 synthetic growth medium. Conversely, the exposure to the same range of doses of sapintoxin A (SAP A; a fluorescent phorbol ester activating the Ca2+/phospholipid-dependent protein kinase [PK-C]) without acting by itself either as a complete or as a second-stage tumour promoter) enhanced the proliferative activity of primary hepatocytes only on condition that a high level of Ca2+ was present in the growth medium. On the other hand, studies on the kinetics of the inhibition of new DNA synthesis showed that the induction of the G0/G1 and G1/S transitions by TPA in hepatocytes incubated in the Ca2+-devoid HiWoBa20000 medium still required cellular Ca2+-, CaM-, and PK-C-dependent metabolic events. Hence, the diverse conditioning of the mitogenic activity of tumour promoting and non-promoting phorbol esters by the level of extracellular Ca2+ suggests as a quite likely event the involvement in the process of differently Ca2+-dependent isoenzymes of their receptor PK-C.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Abbreviations

Ca2+ :

calcium

CaM:

calmodulin

CsA:

cyclosporin A

H-7:

1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine

La3+ :

lanthanum

PK-C:

(Ca2+/phospholipid-dependent)protein kinase C

R-24571:

calmidazolium

SAP A:

sapintoxin A

TFP:

trifluoperazine

TPA:

12-O-tetradecanoylphorbol- 13-acetate

TLCK:

N-α-p-tosyl-L-lysine chloromethyl ketone

TMB-8:

3,4,5-trimethoxybenzoic acid 8-(diethylamino) octyl ester

W-13:

N-(4-aminobutyl)- 5- chloro-2-naphthalene sulfonamide.

References

  1. E. Hecker, N. E. Fusenig, W. Kunz, F. Marks, and H. Thielmann, Cocarcinogenesis and biological effects of tumor promoters, in: “Carcinogenesis. A Comprehnsive Survey,” Raven Press, New York, vol. 7, (1982).

    Google Scholar 

  2. R. Schulte-Hermann, G. Ohde, J. Schuppler, and I. Timmerman-Trosiener, Enhanced proliferation of putative preneoplastic cells in rat liver following treatment with the tumor promoters phenobarbital, hexachlorocyclohexane, steroid compounds, and nafenopin, Cancer Res. 41: 2556 (1981).

    PubMed  CAS  Google Scholar 

  3. U. Armato, P. G. Andreis, and F. Romano, Exogenous Cu, Zn superoxide dismutase suppresses the stimulation of neonatal rat hepatocytes’ growth by tumor promoters, Carcinogenesis 5: 1547 (1984).

    Article  PubMed  CAS  Google Scholar 

  4. U. Armato, P. G. Andreis, and F. Romano, The stimulation by the tumor promoters 12-O-tetradecanoylphorbol-l3-acetate and phenobarbital of the growth of primary neonatal rat hepatocytes, Carcinogenesis 6: 811 (1985).

    Article  PubMed  CAS  Google Scholar 

  5. U. Armato, F. Romano, and P. G. Andreis, The tumor promoters TPA, phenobarbital, and nafenopin and the prostaglandins of A, E, and F series overcome the G1/S block imposed by extracellular calcium deprivation on neonatal rat hepatocytes, Prostaglan. Leuk. Med. 13: 237 (1984).

    Article  CAS  Google Scholar 

  6. F. Romano, C. Marchesini, L. Paccagnella, and U. Armato, Antioxidants and blockers of arachidonate metabolism inhibit the mitogenic effects of TPA in hepatocytes:differences in the operative mechanisms according to the cell cycle setting, Cell Biol. Int. Rep. 10: 797 (1986).

    Article  PubMed  CAS  Google Scholar 

  7. F. Romano, P. G. Andreis, C. Marchesini, L. Paccagnella, and U. Armato, Studies on the mechanisms by which tumor promoters stimulate the growth of primary neonatal rat hepatocytes, Toxicol. Pathol. 14: 375 (1986).

    CAS  Google Scholar 

  8. J. Braz, and M. C. Lechner, ADP-ribosylation of nuclear proteins is increased by phenobarbital. Identification of the ADP-ribosylated histone fractions in rat liver nuclei. FEES Lett. 199: 164 (1986).

    Article  CAS  Google Scholar 

  9. F. Romano, L. Menapace, and U. Armato, Inhibitors of ADP-ribosyl transferase suppress the mitogenic actions exerted by tumor promoters, but not those evoked by peptide mitogens, in primary neonatal rat hepatocytes, Carcinogenesis 9: 2147 (1988).

    Article  PubMed  CAS  Google Scholar 

  10. S. M. Fischer, G. L. Gleason, L. G. Hardin, J. S. Bohrman, and T. J. Slaga, Prostaglandin modulation of skin tumor promotion, Carcinogenesis 1: 245 (1980).

    Article  PubMed  CAS  Google Scholar 

  11. R. Kato, T. Nakadate, S. Yamamoto, and T. Sugimura, Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion and ornithine decarboxylase activity by quercetin: possible involvement of lipoxygenase inhibition, Carcinogenesis 4: 1301 (1983).

    Article  PubMed  CAS  Google Scholar 

  12. T. Nakadate, s. Yamamoto, M. Ishii, and R. Kato, Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity by phospholipase A2 inhibitors and lipoxygenase inhibitor. Cancer Res. 42: 2841 (1982).

    PubMed  CAS  Google Scholar 

  13. M. Veigl, T. C. Vanaman, and W. C. Sedwick, Calcium and calmodulin in cell growth and transformation, Biochim. Biophys. Acta 738: 21 (1984).

    PubMed  CAS  Google Scholar 

  14. K. Hirasawa, and Y. Nishizuka, Phosphatidylinositol turnover in receptor mechanism and signal transduction, Ann. Rev. Pharmacol. Toxicol. 25: 147 (1985).

    Article  CAS  Google Scholar 

  15. U. Kikkawa, and Y. Nishizuka, The role of protein kinase C in transmembrane signalling, Annu. Rev. Cell Biol. 2: 149 (1986).

    Article  PubMed  CAS  Google Scholar 

  16. H. Fujiki, Y. Tanaka, R. Miyake, U. Kikkawa, Y. Nishizuka, and T. Sugimura, Activation of calcium-activated, phospholipid-dependent protein kinase by new classes of tumor promoters: teleocidin and debromoaplysiatoxin, Biochem. Biophys. Res. Commun. 120: 339 (1984).

    Article  PubMed  CAS  Google Scholar 

  17. R. Miyake, Y. Tanaka, T. Tsuda, K. Kaibuchi, U. Kikkawa, and Y. Nishizuka, Activation of protein kinase C by a non-phorbol tumor promoter, mezerein, Biochem. Bhiophys. Res. Commun. 121: 649 (1984).

    Article  PubMed  CAS  Google Scholar 

  18. E. Hecker, Cell membrane associated protein kinase C as a receptor of diterpene ester co-carcinogens of the tumor promoter type and the phenotypic expression of tumors, Arzneim.-Forsch./Drug Res. 35: 1890 (1985).

    CAS  Google Scholar 

  19. C. Cochet, M. Keramidas, C. Souvignet, and E. M. Chambaz, Phorbol ester-induced alteration of protein kinase C catalytic properties occurs at the membrane level and is not reproduced by physiological stimuli, Biochem. Biophys. Res. Commun. 138: 1283 (1986).

    Article  PubMed  CAS  Google Scholar 

  20. J. F. Whitfield, J. P. Durkin D. J. Franks, L. P. Kleine, L. Raptis, R. H. Rixon, M. Sikoraka, and P. R. Walker, Calcium, cyclic AMP, and protein kinase C. Partners in mitogenesis, Cancer Metast. Rev. 5: 205 (1987).

    Article  CAS  Google Scholar 

  21. U. Kikkawa, A, Kishimoto, and Y. Nishizuka, The protein kinase C family: heterogeneity and its implications, Annu. Rev. Biochem. 58: 31 (1989).

    Article  PubMed  CAS  Google Scholar 

  22. F. J. Evans, and M. C. Edwards, Activity correlations in the phorbol ester series, Bot. J. Linnean Soc. 94: 231 (1987).

    Article  Google Scholar 

  23. G. Brooks, A. T. Evans, A. Aitken, and F. J. Evans, A fluorescent phorbol ester that is a potent activator of protein kinase C but is not a tumor-promoter, Cancer Lett. 38: 165 (1987).

    Article  PubMed  CAS  Google Scholar 

  24. G. Brooks, A. Tudor Evans, A. Aitken, and F. J. Evans, Tumor-promoting and hyperplastic effects of phorbol and daphnane esters in CD-1 mouse skin and a synergistic effect of calcium ionophore with the non-promoting activator of protein kinase C, sapintoxin A, Carcinogenesis 10: 283 (1989).

    Article  PubMed  CAS  Google Scholar 

  25. M. C. Edwards, S. E. Taylor, E. M. Williamson, and F. J. Evans, New phorbol and deoxyphorbol esters:isolation and relative potencies in inducing platelet aggregation and erythema of skin. Acta Pharmacol. Toxicol. 53: 177 (1983).

    Article  CAS  Google Scholar 

  26. G. Brooks, N. A. Morrice, C. Ellis, A. Aitken, A. T. Evans, and F. J. Evans, Toxic phorbol esters from the Chinese tallow (Sapium sebiferum) stimulate protein kinase C, Toxicon 25: 1229 (1987).

    Article  PubMed  CAS  Google Scholar 

  27. J. D. Yager Jr., M. W. Pariza, J. E. Becker, and R. Van Potter, DNA synthesis in primary cultures of parenchymal cells isolated from regenerating rat liver, in: “Liver Regeneration After Experimental Injury,” R. Lesch and W. Reutter, eds., Stratton Intercontinental Medical Book Corporation, New York, (1975).

    Google Scholar 

  28. U. Armato, P. G. Andreis, E. Draghi, E. Negri, L. Mengato, and G. Neri, Studies on the persistence of differentiated functions in rat hepatocytes set into primary tissue culture. II. Production of specific exportable proteins and the effects of purine cyclic nucleotides: an immunofluorescent study, In Vitro 14:838 (1978).

    Article  PubMed  CAS  Google Scholar 

  29. U. Armato, P. G. Andreis, and J. F. Whitfield, The calcium-dependence of the stimulation of neonatal hepatocyte DNA synthesis and division by epidermal growth factor, glucagon, and insulin, Chem.-Biol. Interactions 45: 203 (1983).

    Article  CAS  Google Scholar 

  30. C. H. Evans, Interesting and useful biochemical properties of lanthanides, Trends Biochem. Sci. 12: 445 (1983).

    Article  Google Scholar 

  31. R. A. Janis, and D. J. Triggle, New Developments in calcium channel antagonists, J. Biol. Chem. 26: 775 (1983).

    CAS  Google Scholar 

  32. A. W. M. Simpson, T. J. Hallam, and T. J. Rink, TMB-8 inhibits secretion evoked by phorbol ester at basal cytoplasmic free calcium in quin2-loaded platelets much more effectively than it inhibits thrombin-induced calcium mobilization, FEBS Lett. 176: 139 (1984).

    Article  PubMed  CAS  Google Scholar 

  33. H. van Belle, R-24571: a potent inhibitor of calmodulin-activated enzymes, Cell Calcium 2: 483 (1981).

    Article  Google Scholar 

  34. A. D. Hess, P. M. Colombani, and A. H. Esa, Cyclosporin and the immune response: basic aspects, CRC Crit. Rev. Immunol. 6: 123 (1986).

    CAS  Google Scholar 

  35. J. F. Juo, R. L. Raynor, G. J. Mazzei, R. Schatzman, R. S. Turner, and W. R. Kern, Cobra polypeptide cytotoxin I and marine worm polypeptide cytotoxin A-IV are potent and selective inhibitors of phospholipid-sensitive Ca2+-dependent protein kinase, FEBS Lett. 153: 183 (1983).

    Article  Google Scholar 

  36. D. H. Solomon, C. A. O’Brian, and I. B. Weinstein, N-α-tosyl-L-lysine chloromethyl ketone and N-α-tosyl-L-phenylalanine chloromethyl ketone inhibit protein kinase C, FEBS Lett. 190: 342 (1985).

    Article  PubMed  CAS  Google Scholar 

  37. G. J. Mazzei, R. C. Schatzman, R. S. Turner, W. R. Vogler, and J. F. Kuo, Phospholipid-sensitive Ca2+-dependent protein kinase inhibition by R-24571, a calmodulin antagonist, Biochem. Pharmacol. 33: 125 (1984).

    Article  PubMed  CAS  Google Scholar 

  38. C. A. O’Brian, R. M. Liskamp, D. H. Solomon, and I. B. Weistein, Inhibition of protein kinase C by tamoxifen, Cancer Res. 45: 2462 (1985).

    PubMed  Google Scholar 

  39. K. Kimura, K. Sakurada, and N. Katoh, Inhibition by gossypol of phospholipid-sensitive Ca2+-dependent protein kinase from pig testis, Biochim. Biophys. Acta 839: 276 (1985).

    Article  PubMed  CAS  Google Scholar 

  40. C. D. Wright, and M. D. Hoffman, The protein kinase C inhibitors H-7 and H-9 fail to inhibit human neutrophil activation, Biochem. Biophys. Res. Commun. 135: 749 (1986).

    Article  PubMed  CAS  Google Scholar 

  41. V. Della Bianca, M. Grzeskowiak, P. De Togni, M. Cassatella, and F. Rossi, Inhibition by verapamil of neutrophil responses to formylmethionylalanine and phorbol myristate acetate. Mechanism involving Ca2+ changes, cyclic AMP, and protein kinase C, Biochim. Biophys. Acta 845: 223 (1985).

    Article  PubMed  Google Scholar 

  42. H. S. Earp, J. R. Hepler, L. A. Petch, A. Miller, A. R. Berry, J. A. Harris, V. W. Raymond, B. K. McCune, L. W. Lee, J. W. Grisham, and T. K. Harden, Epidermal growth factor (EGF) and hormones stimulate phosphoinositide hydrolysis and increase EGF receptor protein synthesis and mRNA levels in rat liver epithelial cells. Evidence for protein kinase C-dependent and -independent pathways, J. Biol. Chem. 263: 13868 (1988).

    PubMed  CAS  Google Scholar 

  43. M. D. Houslay, Insulin, glucagon, and the receptor-mediated control of cyclic AMP concentrations in liver, Biochem. Soc. Trans. 14: 183 (1986).

    PubMed  CAS  Google Scholar 

  44. M. Acevedoduncan, D. R. Cooper, M. L. Standaert, and R. V. Farese, Immunological evidence that insulin activates protein kinase C in Bc3H-1 myocytes, FEES Lett. 244: 174 (1989).

    Article  CAS  Google Scholar 

  45. I. Kojima, K. Kojima, and H. Rasmussen, Role of calcium and cyclic AMP in the action of adrenocorticotropin on aldosterone secretion, J. Biol. Chem. 260: 4248 (1985).

    PubMed  CAS  Google Scholar 

  46. B. R. Chakravarthy, D. J. Franks, J. F. Whitfield, and J. P. Durkin, A novel method for measuring protein kinase C activity in a native membrane-associated state, Biochem. Biophys. Res. Commun. 160: 340 (1989).

    Article  PubMed  CAS  Google Scholar 

  47. L. G. Garland, R. W. Bonser, and N. T. Thompson, Protein kinase C inhibitors are not selective, Trends Pharmacol. Sci. 8: 334 (1987).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Anatomy and Histology, The School of Medicine, University of Verona, I-37134, Verona, Italy

    L. Menapace, C. Zuch, M. F. Romano, A. Tudor Evans, F. J. Evans & U. Armato

  2. Deparment of Pharmacognosy, The School of Medicine, University of London, WC1N 1AX, London, UK

    A. Tudor Evans & F. J. Evans

Authors
  1. L. Menapace
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Zuch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. F. Romano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Tudor Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. J. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. U. Armato
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of Cagliari, Cagliari, Italy

    Amedeo Columbano  & Paolo Pani  & 

  2. University of Sassari, Sassari, Italy

    Francesco Feo  & Rosa Pascale  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1991 Springer Science+Business Media New York

About this chapter

Cite this chapter

Menapace, L., Zuch, C., Romano, M.F., Evans, A.T., Evans, F.J., Armato, U. (1991). The Different Calcium Requirements of the Mitogenic Effects Elicited in Primary Neonatal Rat Hepatocytes by the Diterpene Phorbol Esters 12-O-Tetradecanoylphorbol-13-Acetate and Sapintoxin A. In: Columbano, A., Feo, F., Pascale, R., Pani, P. (eds) Chemical Carcinogenesis 2. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3694-9_23

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-3694-9_23

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6642-3

  • Online ISBN: 978-1-4615-3694-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation