Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1992 Dec;66(6):1077–1082. doi: 10.1038/bjc.1992.413

Effects of staurosporine, K 252a and other structurally related protein kinase inhibitors on shape and locomotion of Walker carcinosarcoma cells.

A Zimmermann 1, H Keller 1
PMCID: PMC1978012  PMID: 1457347

Abstract

The structure/activity relationship of the protein kinase inhibitors, staurosporine and K 252a and their analogues on motility of Walker carcinosarcoma cells has been studied in vitro. Staurosporine and K 252a, similar to phorbol myristate acetate (PMA) and diacylglycerols, suppress cell polarity and locomotor activity of Walker carcinosarcoma cells. Staurosporine inhibits spontaneous and colchicine-induced front-tail polarity (ID50 of about 6.0 x 10(-8) M) as well as spontaneous and colchicine-stimulated locomotion at 10(-7) M. K 252a suppresses cell polarity (ID50 of about 4.5 x 10(-6) M) and inhibits spontaneous and colchicine-stimulated locomotion at 10(-5) M, but suppression of locomotor activity is not complete in the presence of colchicine. CGP 41251, a staurosporine derivative with a much higher specificity for protein kinase C (PKC) than staurosporine, induces a dose-dependent increase in the proportion of polarised cells, and stimulates cell locomotion. Two K252a analogues, KT 5720 and KT 5822, which act preferentially on cyclic nucleotide-dependent protein kinases, and CGP 42700, an inactive staurosporine analogue, had no effect on cell polarity and locomotion. The findings suggest that protein kinase inhibitors acting preferentially on PKC may be of interest in pharmacological regulation of tumour cell locomotion.

Full text

PDF
1079

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bacher N., Zisman Y., Berent E., Livneh E. Isolation and characterization of PKC-L, a new member of the protein kinase C-related gene family specifically expressed in lung, skin, and heart. Mol Cell Biol. 1991 Jan;11(1):126–133. doi: 10.1128/mcb.11.1.126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bell R. M., Burns D. J. Lipid activation of protein kinase C. J Biol Chem. 1991 Mar 15;266(8):4661–4664. [PubMed] [Google Scholar]
  3. Chiarugi V., Bruni P., Pasquali F., Magnelli L., Basi G., Ruggiero M., Farnararo M. Synthesis of diacylglycerol de novo is responsible for permanent activation and down-regulation of protein kinase C in transformed cells. Biochem Biophys Res Commun. 1989 Oct 31;164(2):816–823. doi: 10.1016/0006-291x(89)91532-5. [DOI] [PubMed] [Google Scholar]
  4. Chou C. F., Omary M. B. Phorbol acetate enhances the phosphorylation of cytokeratins 8 and 18 in human colonic epithelial cells. FEBS Lett. 1991 Apr 22;282(1):200–204. doi: 10.1016/0014-5793(91)80477-k. [DOI] [PubMed] [Google Scholar]
  5. Dlugosz A. A., Yuspa S. H. Staurosporine induces protein kinase C agonist effects and maturation of normal and neoplastic mouse keratinocytes in vitro. Cancer Res. 1991 Sep 1;51(17):4677–4684. [PubMed] [Google Scholar]
  6. Fridman R., Lacal J. C., Reich R., Bonfil D. R., Ahn C. H. Differential effects of phorbol ester on the in vitro invasiveness of malignant and non-malignant human fibroblast cells. J Cell Physiol. 1990 Jan;142(1):55–60. doi: 10.1002/jcp.1041420108. [DOI] [PubMed] [Google Scholar]
  7. Gopalakrishna R., Barsky S. H. Tumor promoter-induced membrane-bound protein kinase C regulates hematogenous metastasis. Proc Natl Acad Sci U S A. 1988 Jan;85(2):612–616. doi: 10.1073/pnas.85.2.612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gschwendt M., Leibersperger H., Marks F. Differentiative action of K252a on protein kinase C and a calcium-unresponsive, phorbol ester/phospholipid-activated protein kinase. Biochem Biophys Res Commun. 1989 Nov 15;164(3):974–982. doi: 10.1016/0006-291x(89)91765-8. [DOI] [PubMed] [Google Scholar]
  9. Hidaka H., Inagaki M., Kawamoto S., Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984 Oct 9;23(21):5036–5041. doi: 10.1021/bi00316a032. [DOI] [PubMed] [Google Scholar]
  10. Kase H., Iwahashi K., Nakanishi S., Matsuda Y., Yamada K., Takahashi M., Murakata C., Sato A., Kaneko M. K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem Biophys Res Commun. 1987 Jan 30;142(2):436–440. doi: 10.1016/0006-291x(87)90293-2. [DOI] [PubMed] [Google Scholar]
  11. Keller H. U. Motility, cell shape, and locomotion of neutrophil granulocytes. Cell Motil. 1983;3(1):47–60. doi: 10.1002/cm.970030105. [DOI] [PubMed] [Google Scholar]
  12. Keller H. U., Zimmermann A., Cottier H. Phorbol myristate acetate (PMA) suppresses polarization and locomotion and alters F-actin content of Walker carcinosarcoma cells. Int J Cancer. 1985 Oct 15;36(4):495–501. doi: 10.1002/ijc.2910360414. [DOI] [PubMed] [Google Scholar]
  13. Keller H. U., Zimmermann A., Niggli V. Diacylglycerols and the protein kinase inhibitor H-7 suppress cell polarity and locomotion of Walker 256 carcinosarcoma cells. Int J Cancer. 1989 Nov 15;44(5):934–939. doi: 10.1002/ijc.2910440531. [DOI] [PubMed] [Google Scholar]
  14. Keller H. U., Zimmermann A. Shape changes and chemokinesis of Walker 256 carcinosarcoma cells in response to colchicine, vinblastine, nocodazole and taxol. Invasion Metastasis. 1986;6(1):33–43. [PubMed] [Google Scholar]
  15. Lindner D., Gschwendt M., Marks F. Down-regulation of protein kinase C in Swiss 3T3 fibroblasts is independent of its phosphorylating activity. Biochem Biophys Res Commun. 1991 May 15;176(3):1227–1231. doi: 10.1016/0006-291x(91)90416-5. [DOI] [PubMed] [Google Scholar]
  16. Meyer T., Regenass U., Fabbro D., Alteri E., Rösel J., Müller M., Caravatti G., Matter A. A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int J Cancer. 1989 May 15;43(5):851–856. doi: 10.1002/ijc.2910430519. [DOI] [PubMed] [Google Scholar]
  17. Mochly-Rosen D., Khaner H., Lopez J. Identification of intracellular receptor proteins for activated protein kinase C. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3997–4000. doi: 10.1073/pnas.88.9.3997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Niggli V., Keller H. On the role of protein kinases in regulating neutrophil actin association with the cytoskeleton. J Biol Chem. 1991 Apr 25;266(12):7927–7932. [PubMed] [Google Scholar]
  19. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  20. Omary M. B., Baxter G. T., Chou C. F., Riopel C. L., Lin W. Y., Strulovici B. PKC epsilon-related kinase associates with and phosphorylates cytokeratin 8 and 18. J Cell Biol. 1992 May;117(3):583–593. doi: 10.1083/jcb.117.3.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Preiss J., Loomis C. R., Bishop W. R., Stein R., Niedel J. E., Bell R. M. Quantitative measurement of sn-1,2-diacylglycerols present in platelets, hepatocytes, and ras- and sis-transformed normal rat kidney cells. J Biol Chem. 1986 Jul 5;261(19):8597–8600. [PubMed] [Google Scholar]
  22. Roos F. J., Zimmermann A., Keller H. U. Effect of phorbol myristate acetate and the chemotactic peptide fNLPNTL on shape and movement of human neutrophils. J Cell Sci. 1987 Oct;88(Pt 3):399–406. doi: 10.1242/jcs.88.3.399. [DOI] [PubMed] [Google Scholar]
  23. Rüegg U. T., Burgess G. M. Staurosporine, K-252 and UCN-01: potent but nonspecific inhibitors of protein kinases. Trends Pharmacol Sci. 1989 Jun;10(6):218–220. doi: 10.1016/0165-6147(89)90263-0. [DOI] [PubMed] [Google Scholar]
  24. Sako T., Tauber A. I., Jeng A. Y., Yuspa S. H., Blumberg P. M. Contrasting actions of staurosporine, a protein kinase C inhibitor, on human neutrophils and primary mouse epidermal cells. Cancer Res. 1988 Aug 15;48(16):4646–4650. [PubMed] [Google Scholar]
  25. Takenaga K., Takahashi K. Effects of 12-O-tetradecanoylphorbol-13-acetate on adhesiveness and lung-colonizing ability of Lewis lung carcinoma cells. Cancer Res. 1986 Jan;46(1):375–380. [PubMed] [Google Scholar]
  26. Tusupov O. K., Severin S. E., Shvets V. I. Proteolytic fragment of protein kinase C (kinase M) phosphorylates in vitro phosphatidylinositol-4-phosphate. Biochem Biophys Res Commun. 1991 May 15;176(3):1007–1013. doi: 10.1016/0006-291x(91)90382-h. [DOI] [PubMed] [Google Scholar]
  27. Weyman C. M., Taparowsky E. J., Wolfson M., Ashendel C. L. Partial down-regulation of protein kinase C in C3H 10T 1/2 mouse fibroblasts transfected with the human Ha-ras oncogene. Cancer Res. 1988 Nov 15;48(22):6535–6541. [PubMed] [Google Scholar]
  28. Wolf M., Baggiolini M. The protein kinase inhibitor staurosporine, like phorbol esters, induces the association of protein kinase C with membranes. Biochem Biophys Res Commun. 1988 Aug 15;154(3):1273–1279. doi: 10.1016/0006-291x(88)90277-x. [DOI] [PubMed] [Google Scholar]
  29. Zimmermann A., Gehr P., Keller H. U. Diacylglycerol-induced shape changes, movements and altered F-actin distribution in human neutrophils. J Cell Sci. 1988 Aug;90(Pt 4):657–666. doi: 10.1242/jcs.90.4.657. [DOI] [PubMed] [Google Scholar]
  30. Zimmermann A., Keller H. U. Locomotion of tumor cells as an element of invasion and metastasis. Biomed Pharmacother. 1987;41(6):337–344. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES