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. 1988 Jul;94(3):917–923. doi: 10.1111/j.1476-5381.1988.tb11604.x

Analysis of the stimulative effect of thapsigargin, a non-TPA-type tumour promoter, on arachidonic acid metabolism in rat peritoneal macrophages.

K Ohuchi 1, T Sugawara 1, M Watanabe 1, N Hirasawa 1, S Tsurufuji 1, H Fujiki 1, S B Christensen 1, T Sugimura 1
PMCID: PMC1854014  PMID: 3140994

Abstract

1. At concentrations above 10 ng ml-1, the tumour promoter thapsigargin stimulates the release of radioactivity from [3H]-arachidonic acid-labelled macrophages harvested from rat peritoneal cavity. 2. The release of radioactivity from prelabelled macrophages was augmented more than additively when the cells were incubated in the medium containing both thapsigargin (10 ng ml-1) and other tumour promoters (10 ng ml-1), such as 12-O-tetradecanoylphorbol-13-acetate (TPA), teleocidin and aplysiatoxin. 3. Thapsigargin required extracellular Ca2+ for the stimulation of arachidonic acid release, while TPA did not. 4. Cytoplasmic free calcium level was increased by thapsigargin treatment but not by TPA treatment. 5. An inhibitor of protein kinases, H-7 inhibited the effect of TPA dose-dependently, whereas H-7 did not inhibit that of thapsigargin. 6. These results suggest that thapsigargin stimulates arachidonic acid release by a mechanism different from that of TPA, viz by acting as a selective Ca2+ mobilizer, but not by activating protein kinase C as TPA does.

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Selected References

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  1. Ali H., Christensen S. B., Foreman J. C., Pearce F. L., Piotrowski W., Thastrup O. The ability of thapsigargin and thapsigargicin to activate cells involved in the inflammatory response. Br J Pharmacol. 1985 Jul;85(3):705–712. doi: 10.1111/j.1476-5381.1985.tb10567.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blumberg P. M., Jaken S., König B., Sharkey N. A., Leach K. L., Jeng A. Y., Yeh E. Mechanism of action of the phorbol ester tumor promoters: specific receptors for lipophilic ligands. Biochem Pharmacol. 1984 Mar 15;33(6):933–940. doi: 10.1016/0006-2952(84)90448-9. [DOI] [PubMed] [Google Scholar]
  3. Fujiki H., Suganuma M., Matsukura N., Sugimura T., Takayama S. Teleocidin from Streptomyces is a potent promoter of mouse skin carcinogenesis. Carcinogenesis. 1982;3(8):895–898. doi: 10.1093/carcin/3.8.895. [DOI] [PubMed] [Google Scholar]
  4. Fujiki H., Suganuma M., Nakayasu M., Hoshino H., Moore R. E., Sugimura T. The third class of new tumor promoters, polyacetates (debromoaplysiatoxin and aplysiatoxin), can differentiate biological actions relevant to tumor promoters. Gan. 1982 Jun;73(3):495–497. [PubMed] [Google Scholar]
  5. Fujiki H., Tanaka Y., Miyake R., Kikkawa U., Nishizuka Y., Sugimura T. Activation of calcium-activated, phospholipid-dependent protein kinase (protein kinase C) by new classes of tumor promoters: teleocidin and debromoaplysiatoxin. Biochem Biophys Res Commun. 1984 Apr 30;120(2):339–343. doi: 10.1016/0006-291x(84)91259-2. [DOI] [PubMed] [Google Scholar]
  6. Hakii H., Fujiki H., Suganuma M., Nakayasu M., Tahira T., Sugimura T., Scheuer P. J., Christensen S. B. 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. 1986;111(3):177–181. doi: 10.1007/BF00389230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Kano S., Iizuka T., Ishimura Y., Fujiki H., Sugimura T. Stimulation of superoxide anion formation by the non-TPA type tumor promoters palytoxin and thapsigargin in porcine and human neutrophils. Biochem Biophys Res Commun. 1987 Mar 13;143(2):672–677. doi: 10.1016/0006-291x(87)91406-9. [DOI] [PubMed] [Google Scholar]
  9. Kawamoto S., Hidaka H. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine (H-7) is a selective inhibitor of protein kinase C in rabbit platelets. Biochem Biophys Res Commun. 1984 Nov 30;125(1):258–264. doi: 10.1016/s0006-291x(84)80362-9. [DOI] [PubMed] [Google Scholar]
  10. Ohuchi K., Hirasawa N., Takahashi C., Watanabe M., Tsurufuji S., Fujiki H., Suganuma M., Hakii H., Sugimura T., Christensen S. B. Synergistic stimulation of histamine release from rat peritoneal mast cells by 12-O-tetradecanoylphorbol 13-acetate (TPA)-type and non-TPA-type tumor promoters. Biochim Biophys Acta. 1986 Jun 16;887(1):94–99. doi: 10.1016/0167-4889(86)90127-8. [DOI] [PubMed] [Google Scholar]
  11. Ohuchi K., Kamada Y., Levine L., Tsurufuji S. Glycyrrhizin inhibits prostaglandin E2 production by activated peritoneal macrophages from rats. Prostaglandins Med. 1981 Nov;7(5):457–463. doi: 10.1016/0161-4630(81)90033-1. [DOI] [PubMed] [Google Scholar]
  12. Ohuchi K., Sugawara T., Watanabe M., Hirasawa N., Tsurufuji S., Fujiki H., Sugimura T., Christensen S. B. Stimulation of arachidonic acid metabolism in rat peritoneal macrophages by thapsigargin, a non-(12-O-tetradecanoylphorbol-13-acetate) (TPA)-type tumor promoter. J Cancer Res Clin Oncol. 1987;113(4):319–324. doi: 10.1007/BF00397715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ohuchi K., Watanabe M., Takahashi C., Hayashi Y., Hirasawa N., Tsurufuji S., Fujiki H., Sugimura T. Analysis of tumor-promoter-induced inflammation in rats: participation of histamine and prostaglandin E2. Biochim Biophys Acta. 1987 Aug 13;925(2):156–163. [PubMed] [Google Scholar]
  14. Ohuchi K., Watanabe M., Yoshizawa K., Tsurufuji S., Fujiki H., Suganuma M., Sugimura T., Levine L. 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. 1985 Mar 27;834(1):42–47. doi: 10.1016/0005-2760(85)90174-2. [DOI] [PubMed] [Google Scholar]
  15. Rasmussen U., Brøogger Christensen S., Sandberg F. Thapsigargine and thapsigargicine, two new histamine liberators from Thapsia garganica L. Acta Pharm Suec. 1978;15(2):133–140. [PubMed] [Google Scholar]
  16. Rickard J. E., Sheterline P. Evidence that phorbol ester interferes with stimulated Ca2+ redistribution by activating Ca2+ efflux in neutrophil leucocytes. Biochem J. 1985 Nov 1;231(3):623–628. doi: 10.1042/bj2310623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Thastrup O., Foder B., Scharff O. The calcium mobilizing tumor promoting agent, thapsigargin elevates the platelet cytoplasmic free calcium concentration to a higher steady state level. A possible mechanism of action for the tumor promotion. Biochem Biophys Res Commun. 1987 Feb 13;142(3):654–660. doi: 10.1016/0006-291x(87)91464-1. [DOI] [PubMed] [Google Scholar]
  18. Thastrup O., Linnebjerg H., Bjerrum P. J., Knudsen J. B., Christensen S. B. The inflammatory and tumor-promoting sesquiterpene lactone, thapsigargin, activates platelets by selective mobilization of calcium as shown by protein phosphorylations. Biochim Biophys Acta. 1987 Jan 19;927(1):65–73. doi: 10.1016/0167-4889(87)90066-8. [DOI] [PubMed] [Google Scholar]
  19. Tsien R. Y., Pozzan T., Rink T. J. Calcium homeostasis in intact lymphocytes: cytoplasmic free calcium monitored with a new, intracellularly trapped fluorescent indicator. J Cell Biol. 1982 Aug;94(2):325–334. doi: 10.1083/jcb.94.2.325. [DOI] [PMC free article] [PubMed] [Google Scholar]

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