Skip to main content
SpringerLink
Log in

Stimulation of prostaglandin E2 production and induction of specific protein synthesis in rat peritoneal macrophages by a tumor promoter staurosporine

  • Original Papers
  • Experimental Oncology
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Staurosporine is a microbial anti-fungal alkaloid having potent inhibitory activity on protein kinase C and is a non 12-O-tetradecanoylphorbol-13-acetate-type tumor promoter in two-stage carcinogenesis experiments in mouse skin. Effects of staurosporine and its structurally related compounds K-252a, KT5720 and KT5822 on prostaglandin E2 production, release of arachidonic acid from membrane phospholipids, and uptake of [35S]methionine into intracellular proteins were examined in rat peritoneal macrophages. Among the four compounds, only staurosporine stimulated the production of prostaglandin E2 and release of arachidonic acid at concentrations of 1 ng/ml and 10 ng/ml. The uptake of [35S]methionine into cellular proteins, estimated to be 120 kDa and 125 kDa molecular mass, was also stimulated by staurosporine treatment, and the uptake was increased in parallel with the increase in prostaglandin E2 production. At higher concentrations (100 ng/ml and 1000 ng/ml), staurosporine inhibited prostaglandin E2 production and did not induce the specific protein synthesis. Other compounds neither stimulated prostaglandin E2 production nor induced specific protein synthesis. K-252a inhibited prostaglandin E2 production at concentrations above 10 ng/ml. These results suggest that the staurosporine-induced proteins might participate in the tumor promotion or at least in the staurosporine-induced stimulation of prostaglandin E2 production.

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

Abbreviations

TPA:

12-O-tetradecanoylphorbol tetradecanoylphorbol-13-acetate 13-acetate

References

  • Bialojan C, Takai A (1988) Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Biochem J 256:283–290

    Google Scholar 

  • Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka Y (1982) Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor promoting phorbol esters. J Biol Chem 257:7847–7851

    Google Scholar 

  • Daniel M, James WD (1978) Isoelectric points of proteins. Anal Biochem 86:620–647

    Google Scholar 

  • Fujiki H, Suganuma M, Matsukura N, Sugimura T, Takayama S (1982) Teleocidin fromStreptomyces is a potent promoter of mouse skin carcinogenesis. Carcinogenesis 3:895–898

    Google Scholar 

  • Fujiki H, Suganuma M, Yoshioka A, Nakayasu M, Endo Y, Shudo K, Takayama S, Moore RE, Sugimura T (1984a) New classes of tumor promoters: teleocidin, aplysiatoxin, and palytoxin. In: Fujiki H, Hecker E, Moore RE, Sugimura T, Weinstein IB (eds) Cellular interactions by environmental tumor promoters. Jpn Sci Soc Press Tokyo/VNU Science Press, Utrecht, pp 37–45

    Google Scholar 

  • Fujiki H, Tanaka Y, Miyake R, Kikkawa U, Nishizuka Y, Sugimura T (1984b) Activation of calcium-activated, phospholipid-dependent protein kinase (protein kinase C) by new classes of tumor promoters: teleocidin and debromoaplysiatoxin. Biochem Biophys Res Commun 120:339–343

    Google Scholar 

  • Fujiki H, Suganuma M, Nakayasu M, Hakii H, Horiuchi T, Takayama S, Sugimura T (1986) Palytoxin is a non-12-O-tetradecanoylphorbol-13-acetate type tumor promoter in two-stage mouse skin carcinogenesis. Carcinogenesis 7:707–710

    Google Scholar 

  • Fujiki H, Suganuma M, Suguri H, Yoshizawa S, Takagi K, Uda N, Wakamatsu K, Yamada K, Murata M, Yasumoto T, Sugimura T (1988) Diarrhetic shellfish toxin, dinophysistoxin-1, is a potent tumor promoter on mouse skin. Jpn J Cancer Res 79:1089–1093

    Google Scholar 

  • Gerhard F, Helmut H, Tobias J, Eva B, Michael S, Wolf-Dieter L, Friedrich M (1991) Characterization of an 8-lipoxygenase activity induced by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate in mouse skin in vivo. J Biol Chem 266:5738–5745

    Google Scholar 

  • Hakii H, Fujiki H, Suganuma M, Nakayasu M, Tahira T, Sugimura T, Scheuer PJ, Christensen SB (1986) Thapsigargin, a histamine secretagogue, is a non-12-O-tetradecanoylphorbol-13-acetate(TPA)type tumor promoter in two-stage mouse skin carcinogenesis. J Cancer Res Clin Oncol 111:177–181

    Google Scholar 

  • Hannun YA, Loomis CR, Merrill AH, Bell RM (1986) Sphingosine inhibition of protein kinase C activity and of phorbol dibutylate binding in vitro and in human platelets. J Biol Chem 261:12604–12609

    Google Scholar 

  • Hashimoto S, Hagino A (1989) Staurosporine-induced neurite out-growth in PC12h cells. Exp Cell Res 184:351–359

    Google Scholar 

  • Hecker E (1967) Phorbol esters from croton oil, chemical nature and biological activities. Naturwissenschaften 54:282–284

    Google Scholar 

  • Hidaka H, Inagaki M, Kawamoto S, Sasaki Y (1984) Isoquinoline-sulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry 23:5036–5041

    Google Scholar 

  • Hystead TA, Sim ATR, Carling D, Honnor RC, Tsukitani Y, Cohn P, Hardie DG (1989) Effects of the tumor promoter okadaic acid on intracellular protein phosphorylation and metabolism. Nature 337:78–81

    Google Scholar 

  • Jackson TR, Patterson SI, Thastrup O, Hanley MR (1988) A novel tumour promoter, thapsigargin, transiently increases cytoplasmic free Ca2+ without generation of inositol phosphates in NG115-401L neuronal cells. Biochemistry 253:81–86

    Google Scholar 

  • Janet G, James AC, Keith AC, Curtis W, Perry VH (1991) Endotoxin-induced arachidonic acid metabolism requires de novo protein synthesis and protein kinase C activation. Biochim Biophys Acta 1085:15–20

    Google Scholar 

  • Jonathan L, Marisa W, Michael RH (1991) Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J Biol Chem 266:17067–17071

    Google Scholar 

  • Kase H, Iwahashi K, Matsuda Y (1986) K-252a, a potent inhibitor of protein kinase C from microbial origin. J Antibiot (Tokyo) 39:1059–1065

    Google Scholar 

  • Kase H, Iwahashi K, Nakanishi S, Matsuda Y, Yamada K, Takahashi M, Murakata C, Sato A, Kaneko M (1987) K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem Biophys Res Commun 142:436–440

    Google Scholar 

  • Kikkawa U, Takai Y, Tanaka Y, Miyake R, Nishizuka Y (1983) Protein kinase C as a possible receptor protein of tumor promoting phorbol esters. J Biol Chem 258:11442–11445

    Google Scholar 

  • Koehler L, Hass R, Wessel K, DeWitt DL, Kaever V, Resch K, Goppelt-Struebe M (1990) Altered arachidonic acid metabolism during differentiation of the human monoblastoid cell line U937. Biochim Biophys Acta 1042:395–403

    Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Google Scholar 

  • Loomis CR, Bell RM (1988) Sangivamycin, a nucleoside analogue, is a potent inhibitor of protein kinase C. J Biol Chem 263:1682–1692

    Google Scholar 

  • Matthias G, Andreas JRH, Roselinde H, Wolfgang Z, Hugo K, Burkhard K, Reinhard Z, John AG (1987)sn-1,2-diacylglycerols and phorbol diesters stimulate thromboxane synthesis by de novo synthesis of prostaglandin H synthase in human promyelocytic leukemia cells. J Clin Invest 79:903–911

    Google Scholar 

  • Mike AC, Lynne EO, Theresa MC, Janice D, Stanley TC, John SB (1991) Cloning of a phospholipase A2-activating protein. Proc Natl Acad Sci USA 88:5418–5422

    Google Scholar 

  • O'Brien CA, Liskamp RM, Solomon DH, Weinstein IB (1985) Inhibition of protein kinase C by tamoxifen. Cancer Res 45:2462–2465

    Google Scholar 

  • O'Farrell PH (1975) High resolution two-dimensional electrophoresis of proteins. J Biol Chem 250:4007–4021

    Google Scholar 

  • Ohuchi K, Watanabe M, Yoshizawa K, Tsurufuji S, Fujiki H, Suganuma M, Sugimura T, Levine L (1985) Stimulation of prostaglandin E2 production by 12-O-tetradecanoylphorbol-13-acetate(TPA)-type and non-TPA-type tumor promoters in macrophages and its inhibition by cycloheximide. Biochim Biophys Acta 834:42–47

    Google Scholar 

  • Ohuchi K, Sugawara T, Watanabe M, Hirasawa N, Tsurufuji S, Fujiki H, Sugimura T, Christensen SB (1987) Stimulation of arachidonic acid metabolism in rat peritoneal macrophage by thapsigargin, a non-(12-O-tetradecanoylphorbol-13-acetate)(TPA)-type tumour promoter. J Cancer Res Clin Oncol 113:319–324

    Google Scholar 

  • Ohuchi K, Sugawara T, Watanabe M, Hirasawa N, Tsurufuji S, Fujiki H, Christensen SB, Sugimura T (1988) Analysis of the stimulative effect of thapsigargin, a non-TPA-type tumor promoter, on arachidonic acid metabolism in rat peritoneal macrophages. Br J Pharmacol 94:917–923

    Google Scholar 

  • Ohuchi K, Tamura T, Ohashi M, Watanabe M, Hirasawa N, Tsurufuji S, Fujiki H (1989a) Okadaic acid and dinophysistoxin-1, non-TPA-type tumor promoters, stimulate prostaglandin E2 production in rat peritoneal macrophages. Biochim Biophys Acta 1013:86–91

    Google Scholar 

  • Ohuchi K, Takahashi C, Hirasawa N, Watanabe M, Fujiki H, Tsurufuji S (1989b) Stimulation of histamine release and arachidonic acid metabolism in rat peritoneal mast cells by thapsigargin, a non-TPA-type tumor promoter. Biochim Biophys Acta 1003:9–14

    Google Scholar 

  • Omura S, Iwai Y, Hirano A, Nakagawa A, Awaya J, Tsuchiya H, Takahashi Y, Masuma R (1977) A new alkaloid AM-2282 ofstreptomyces origin taxonomy, fermentation, isolation and preliminary characterization. J Antibiot (Tokyo) 30:275–281

    Google Scholar 

  • Ruth MK, Edda FR, Joseph M, James EP (1991) The Ca2+-sensitive cytosolic phospholipase A2 is a 100 kDa protein in human monoblast U937 cells. J Biol Chem 266:5268–5272

    Google Scholar 

  • Suganuma M, Fujiki H, Suguri H, Yoshizawa S, Hirota M, Nakayasu M, Ojika M, Wakamatsu K, Yamada K, Sugumura T (1988) Okadaic acid: an additional non-phorbol-12-tetradecanoate-13-acetate-type tumor promoter. Proc Natl Acad Sci USA 85:1768–1771

    Google Scholar 

  • Tamaoki T, Nomoto H, Takahashi I, Kato Y, Morimoto M, Tomita F (1986) Staurosporine, a potent inhibitor of phospholipid/Ca2+ dependent protein kinase. Biochem Biophys Res Commun 135:397–402

    Google Scholar 

  • Ueda N, Kaneko S, Yoshimoto T, Yamamoto S (1986) Purification of arachidonate 5-lipoxygenase from porcine leukocytes and its reactivity with hydroperoxyeicosatetraenoic acids. J Biol Chem 261:7982–7988

    Google Scholar 

  • Van Der Ouderaa FJ, Buytenhek M, Nugteren DH, Van Dorp DA (1977) Purification and characterization of prostaglandin endoperoxide synthetase from sheep vesicular glands. Biochim Biophys Acta 487:315–331

    Google Scholar 

  • Watanabe M, Tamura T, Ohashi M, Hirasawa N, Ozeki T, Tsurufuji S, Fujiki H, Ohuchi K (1990) Dual effects of staurosporine on arachidonic acid metabolism in rat peritoneal macrophages. Biochim Biophys Acta 1047:141–147

    Google Scholar 

  • Watson SP, Mcnally J, Shipman LT, Godfrey PP (1988) The action of the protein kinase C inhibitor, staurosporine, on human platelets. Biochem J 249:345–350

    Google Scholar 

  • Yoshizawa S, Fujiki H, Suguri H, Suganuma M, Nakayasu M, Matsuhima R, Sugimura T (1990) Tumor-promoting activity of staurosporine, a protein kinase inhibitor on mouse skin. Cancer Res 50:4974–4978

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tohoku University, Aoba Aramaki, Aoba-ku, Sendai, Miyagi 980, Japan

    Toshiya Tamura, Masako Watanabe, Noriyasu Hirasawa & Kazuo Ohuchi

  2. College of Medical Sciences, Tohoku University, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980, Japan

    Suetsugu Mue

Authors
  1. Toshiya Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masako Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noriyasu Hirasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Suetsugu Mue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kazuo Ohuchi
    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

Tamura, T., Watanabe, M., Hirasawa, N. et al. Stimulation of prostaglandin E2 production and induction of specific protein synthesis in rat peritoneal macrophages by a tumor promoter staurosporine. J Cancer Res Clin Oncol 120, 5–11 (1993). https://doi.org/10.1007/BF01200717

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01200717

Key words

Search

Navigation