Skip to main content
NCBI home page
Journal of Cancer Research and Clinical Oncology logoLink to Journal of Cancer Research and Clinical Oncology
. 1995 Mar;121(3):141–149. doi: 10.1007/BF01198095

Alterations in receptor-mediated kinases and phosphatases during carcinogenesis

David H Crean 1,✉, Charles Liebow 1, Ming-Ting Lee 3, Angela R Kamer 1, Andrew V Schally 4, Thomas S Mang 1
PMCID: PMC12201191  PMID: 7713985

Abstract

Increased phosphorylation in cancers can stimulate growth and up-regulate certain receptors. To test whether the functional response of phosphatase receptors is up-regulated during carcinogenesis, we examined the effects of ligands on net phosphorylation in isolated membranes derived from hamster cheekpouch tissues undergoing malignant transformation. The buccal mucosa of groups of Syrian golden hamsters was exposed thrice weekly to 0.5% dimethylbenzanthracene (DMBA) in acetone for 2–12 weeks to produce premalignant and malignant tissues. Homogenates of these tissues were then incubated with [32P]ATP in the presence of epidermal growth factor (EGF), agonist of somatostatin analogue RC-160, luteinizing-hormone-releasing hormone (LH-RH) [d-Trp6]LH-RH, or combinations of EGF, RC-160, and [d-Trp6]LH-RH. Changes compared to controls in phosphorylation in response to ligands provided estimates of kinase or phosphatase activity. Phosphorylation increased continuously, from the first application of DMBA in a linear fashion, and independently of EGF stimulation. RC-160 and [d-Trp6]LH-RH reduced phosphorylation in vitro. This response occurred in premalignant (weeks 6–10 after DMBA application) as well as malignant tissues (week 12 after DMBA application), but was not significant in normal tissues. The results show a continuous augmentation in phosphatase activity prior to the appearance of cancers, but with a delay in expression following the primary event of increased kinase activity. Significantly less phosphorylation of substrates was induced by both RC-160 and [d-Trp6]LH-RH after in vitro activation by EGF than in the absence of EGF. This suggests that EGF activates latent systems of hormonal receptors. Collectively, these results support the hypothesis that the enhancement of the hormonally stimulated phosphatase in cancers occurs secondarily to the increased kinase activity.

Key words: Somatostatin analogue RC-160, Luteinizing-hormone-releasing hormone [D-Trp6]LH-RH, Receptor kinases, Receptor phosphatases

Abbreviations

EGF

epidermal growth factor

RC-160

somatostatin analogue

[d-Trp6]LH-RH

luteinizing-hormone-releasing harmone

DMBA

dimethylbenzanthracene

Footnotes

This work was supported, in part, by research grants from the American Cancer Society PDT-307, the Margaret Duffey and Robert Cameron Troupe Memorial Fund of the Buffalo General Hospital, and the National Institute of Dental Research

References

  1. Buscail L, Delesque N, Esteve JP, Saint-Laurent N, Prats H, Clerc P, Robberecht P, Bell GI, Liebow C, Schally AV, Vaysse N, Susini C (1994) Stimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by the human SSTR1 and SSTR2 somatostatin receptor subtypes. Proc Natl Acad Sci USA 91:2315–2319 [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Eveson JW (1981) Animal models of intra-oral chemical carcinogensis: A review. J Oral Pathol 10:129–146 [DOI] [PubMed] [Google Scholar]
  3. Hierowski MT, Liebow C, DuSapin K, Schally AV (1985) Stimulation by somatostatin of dephosphorylation of membrane proteins in pancreatic cancer MIA PaCa-2 cell line. FEBS Lett 179:252–256 [DOI] [PubMed] [Google Scholar]
  4. Hunter T (1987) A thousand and one protein kinases. Cell 50:823–829 [DOI] [PubMed] [Google Scholar]
  5. Hunter T (1989) Protein-tyrosine phosphatases: the other side of the coin. Cell 58:1013–1016 [DOI] [PubMed] [Google Scholar]
  6. Keri G, Mezo I, Horvath A, Vadasz Z, Balogh A, Idei M, Vantus T, Teplan I, Mak M, Horvath J, Pal K, Csuka O (1993) Novel somatostatin analogs with tyrosine kinase inhibitory and antitumor activity. Biochem Biophys Res Commun 191:681–687 [DOI] [PubMed] [Google Scholar]
  7. Klarlund JK (1985) Transformation of cells by an inhibitor of phosphatases acting on phosphotyrosine in proteins. Cell 41:707–717 [DOI] [PubMed] [Google Scholar]
  8. Lee MT, Liebow C, Kamer AR, Schally AV (1991) Effects of epidermal growth factor and analogues of luteinizing hormone releasing hormone and somatostatin on phosphorylation and dephosphorylation of tyrosine residues of specific protein substrates in various tumors. Proc Natl Acad Sci USA 88:1656–1660 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Liebow C, Kamer AR (1992) Receptor phosphatases and cancer: models for the therapeutic efficacy of somatostatin and LHRH analogues. Cancer J 5:200–207 [Google Scholar]
  10. Liebow C, Hierowski M, DuSapin K (1986) Hormonal control of pancreatic cancer growth. Pancreas 1:44–48 [DOI] [PubMed] [Google Scholar]
  11. Liebow C, Reilly C, Serrano M, Schally AV (1989) Somatostatin analogues inhibit growth of pancreatic cancer by stimulating tyrosine phosphatase. Proc Natl Acad USA Sci 86:2003–2007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Liebow C, Lee MT, Schally AV (1990) Antitumor effects of somatostatin mediated by the stimulation of tyrosine phosphatase. Metabolism 39S:163–166 [DOI] [PubMed] [Google Scholar]
  13. Liebow C, Lee MT, Kamer AR, Schally AV (1991) Regulation of luteinizing hormone releasing hormone receptor binding by heterologous and autologous receptor stimulated tyrosine phosphorylation. Proc Natl Acad Sci USA 88:2244–2248 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McCarley DJ, Parsons SJ (1987) reduced tyrosine kinase specific activity is associated with hypophosphorylation of pp60c-src in cells infected with avian erythroblastosis virus. Proc Natl Acad Sci USA 84:5793–5797 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Rohrer L, Raulf F, Bruns C, Buettner R, Hofstaedter F, Shule R (1993) Cloning and characterization of a fourth human somatostatin receptor. Proc Natl Acad Sci USA 90:4196–4200 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Schally AV (1988) Oncological applications of somatostatin analogs. Cancer Res 48:6977–6985 [PubMed] [Google Scholar]
  17. Schally AV, Srkalovic G, Szende B, Redding TW, Janaky T, Juhasz A, Korkut E, Cai RZ, Szepeshazi K, Radulovic S, et al (1990) Antitumor effects of analogs of LH-RH and somatostatin: experimental and clinical studies. J Steroid Biochem Mol Biol 37:1061–1067 [DOI] [PubMed] [Google Scholar]
  18. Schally AV, Comaru-Schally AM, Hollander V (1993) Hypothalamic and other peptide hormones. In: Holland JF, Frei E, Bast RC, Kufe DW, Morton DL, Weichselbaum RR (eds) Cancer medicine. Lea & Febiger, Philadelphia, pp 827–840 [Google Scholar]
  19. Wang LM, Myers MG, Sun XJ, Aaronson SA, White M, Pierce JH (1993) IRS-1: essential for insulin-and IL-4-stimulated mitogenesis in hematopoietic cells. Science 261:1591–1594 [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cancer Research and Clinical Oncology are provided here courtesy of Springer

RESOURCES